Serine protease variants having amino acid substitutions

ABSTRACT

The present invention relates to variants of serine proteases having decreased immunogenicity relative to their corresponding wild-type proteases. More particularly, the present invention relates to variants having a modified amino acid sequence of a wild-type amino acid sequence, wherein the modified amino acid sequence comprises a substitution of one or more specifically identified positions corresponding to subtilisin BPN′. The invention further relates to mutant genes encoding such variants and cleaning and personal care compositions comprising such variants.

This application claims the benefit of provisional application No.60/079,397, filed Mar. 26, 1998.

FIELD OF THE INVENTION

The present invention relates to serine protease variants andcompositions comprising the variants which have decreased immunogenicityrelative to their corresponding wild-type serine proteases.

BACKGROUND OF THE INVENTION

Enzymes make up the largest class of naturally occurring proteins. Oneclass of enzyme includes proteases which catalyze the hydrolysis ofother proteins. This ability to hydrolyze proteins has been exploited byincorporating naturally occurring and protein engineered proteases intocleaning compositions, particularly those relevant to laundryapplications.

In the cleaning arts, the mostly widely utilized of these proteases arethe serine proteases. Most of these serine proteases are produced bybacterial organisms while some are produced by other organisms, such asfungi. See Siezen, Roland J. et al., “Homology Modelling and ProteinEngineering Strategy of Subtilases, the Family of Subtilisin-Like SerineProteases”, Protein Engineering, Vol. 4, No. 7, pp. 719-737 (1991).Unfortunately, the efficacy of the wild-type proteases in their naturalenvironment frequently does not translate into the unnatural cleaningcomposition environment. Specifically, protease characteristics such as,for example, thermal stability, pH stability, oxidative stability andsubstrate specificity are not necessarily optimized for utilizationoutside the natural environment of the enzyme.

Several approaches have been employed to alter the wild-type amino acidsequence of serine proteases with the goal of increasing the efficacy ofthe protease in the unnatural wash environment. These approaches includethe genetic redesign of proteases to enhance thermal stability and toimprove oxidation stability under quite diverse conditions.

However, because such genetically engineered proteases are foreign tomammals, they are potential antigens. As antigens, these proteases causeimmunological and allergic responses (herein collectively described asimmunological responses) in mammals. In fact, sensitization to serineproteases has been observed in environments wherein humans are regularlyexposed to the proteases. Such environments include manufacturingfacilities, where employees are exposed to the proteases through suchvehicles as uncontrolled dust or aerosolization. Aerosolization canresult by the introduction of the protease into the lung, which is theroute of protease exposure which causes the most dangerous response.Protease sensitization can also occur in the marketplace, whereconsumers′ repeated use of products containing proteases may cause anallergic reaction.

Furthermore, while genetic engineering has been prominent in thecontinuing search for more highly effective proteases for use in laundryapplications, genetically engineered proteases have been minimallyutilized in personal care compositions and light duty detergents. Aprimary reason for the absence of engineered proteases in products suchas, for example, soaps, gels, body washes, and shampoos, is due to theaforementioned problem of human sensitization leading to undesirableimmunological responses. It would therefore be highly advantageous toprovide a personal care composition which provides the cleansingproperties of engineered proteases with minimized provocation ofimmunological responses.

One approach toward alleviating the immunological activity of a proteaseis through the redesign of one or more epitopes of the protease.Epitopes are those amino acid regions of an antigen which evoke animmunological response through the binding of antibodies or thepresentation of processed antigens to T cells via a majorhistocompatibility complex protein (MHC). Changes in the epitopes canaffect their efficiency as an antigen. See Walsh, B. J. and M. E. H.Howden, “A Method for the Detection of IgE Binding Sequences ofAllergens Based on a Modification of Epitope Mapping”, Journal ofImmunological Methods, Vol. 121, pp. 275-280 (1989).

The present inventors have discovered that those serine proteasescommonly known as subtilisins, including subtilisin BPN′, have aprominent epitope region at amino acid positions 70-84 corresponding toBPN′. The present inventors have herein genetically redesigned suchsubtilisins to alleviate the immunogenic properties attributed to thisepitope region. In so doing, the present inventors have discoveredsubtilisins which evoke a decreased immunological response yet maintaintheir activity as an efficient cleansing protease. Accordingly, thepresent proteases are suitable for use in several types of compositionsincluding, but not limited to, laundry, dish, hard surface, skin care,hair care, beauty care, oral, and contact lens compositions.

SUMMARY OF THE INVENTION

The present invention relates to variants of serine proteases havingdecreased immunogenicity relative to their corresponding wild-typeproteases. More particularly, the present invention relates to variantshaving a modified amino acid sequence of a wild-type amino acidsequence, wherein the modified amino acid sequence comprises asubstitution of one or more of positions 70-84 corresponding tosubtilisin BPN′. The invention further relates to mutant genes encodingsuch variants and cleaning and personal care compositions comprisingsuch variants.

DETAILED DESCRIPTION OF THE INVENTION

The essential components of the present invention are herein describedbelow. Also included are non-limiting descriptions of various optionaland preferred components useful in embodiments of the present invention.

The present invention can comprise, consist of, or consist essentiallyof any of the required or optional components and/or limitationsdescribed herein.

All percentages and ratios are calculated by weight unless otherwiseindicated.

All percentages are calculated based on the total composition unlessotherwise indicated.

All component or composition levels are in reference to the active levelof that component or composition, and are exclusive of impurities, forexample, residual solvents or by-products, that may be present incommercially available sources.

All documents referred to herein, including all patents, patentapplications, and printed publications, are hereby incorporated byreference in their entirety.

As used herein, abbreviations will be used to describe amino acids.Table I provides a list of abbreviations used herein:

TABLE I Amino Acid Three-letter Abbreviation One-letter AbbreviationAlanine Ala A Arginine Arg R Asparagine Asn N Aspartic Acid Asp DCysteine Cys C Glutamine Gln Q Glutamic Acid Glu E Glycine Gly GHistidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K MethionineMet M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr TTryptophan Trp W Tyrosine Tyr Y Valine Val V

Definitions

As used herein, the term “mutation” refers to alterations in genesequences and amino acid sequences produced by those gene sequences.Mutations may be deletions, substitutions, or additions of amino acidresidues to the wild-type protein sequence.

As used herein, the term “wild-type” refers to a protein, hereinspecifically a protease, produced by unmutated organisms.

As used herein, the term “variant” means a protein, herein specificallya protease, having an amino acid sequence which differs from that of thewild-type protease.

As referred to herein, while the variants of the present invention arenot limited to those of subtilisin BPN′, all amino acid numbering iswith reference to the amino acid sequence for subtilisin BPN′ E. J.which is represented by SEQ ID NO:1. The amino acid sequence forsubtilisin BPN′ is further described by Wells, J. A., E. Ferrari, D. J.Henner, D. A. Estell, and E. J. Chen, Nucleic Acids Research, Vol. II,7911-7925 (1983), incorporated herein by reference.

Variants of the Present Invention

The present inventors have discovered an epitope region in serineproteases which corresponds to positions 70-84 of subtilisin BPN′. Thepresent inventors have further discovered that one or more amino acidsubstitutions in the amino acid sequence of a wild-type serine proteaseprovides variants which evoke a deceased allergenic and/or immuneresponse relative to the corresponding wild-type serine protease.

As used herein, a variant may be designated by referring to thesubstituted amino acid positions which characterize the variant.Substitutions are herein indicated by providing the wild-type amino acidresidue, followed by the position number, followed by the substitutedamino acid residue to be substituted. Wherein the substituted amino acidresidue may be any natural amino acid allowed at that particularposition, the symbol “*” is provided. Multiple substitutions comprisinga variant are separated by the symbol “+”. To illustrate, a substitutionof valine for glycine at position 70 is designated either Gly70Val orG70V. An example of a variant having a substitution at both positions 70and 72 may be designated as Gly70Val+Val72Ala or G70V+V72A.

The variants of the present invention are variants of serine proteases.As used herein, the term “serine protease” means a protease which has atleast 50%, and preferably 80%, amino acid sequence identity with thesequences for one or more of a subtilisin-like serine protease. Adiscussion relating to subtilisin-like serine proteases and theirhomologies may be found in Siezen et al., “Homology Modelling andProtein Engineering Strategy of Subtilases, the Family ofSubtilisin-Like Serine Proteases”, Protein Engineering, Vol. 4, No. 7,pp. 719-737 (1991). Preferred serine proteases for mutation includesubtilisin BPN′, subtilisin Carlsberg, subtilisin DY, subtilisin 309,proteinase K, and thermitase. The most preferred serine protease formutation is subtilisin BPN′.

The variants of the present invention are variants of serine proteaseshaving a modified amino acid sequence of a wild-type amino acidsequence, wherein the modified amino acid sequence comprises asubstitution of one or more of positions 70, 71, 72, 73, 74, 75, 76, 77,78, 79, 80, 81, 82, 83, and 84 (70-84) corresponding to BPN′. Morepreferably, the modified amino acid sequence comprises a substitution oftwo or more of these positions. Substitutions at these positions aremade by replacing the wild-type amino acid residue with another naturalamino acid residue such as one given in Table I.

More specifically, wherein the variant has a modified amino acidsequence of a wild-type amino acid sequence comprising a substitution atone position corresponding to positions 70-84 of BPN′:

(a) when the substitution occurs at position 70, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Glu, Phe, His, Ile, Lys, Leu, Met, Pro, Gln, Ser, Thr, Trp, Tyr, andVal;

(b) when the substitution occurs at position 71, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Cys, Gly,Phe, His, Ile, Lys, Leu, Met, Pro, Gln, Ser, Trp, Tyr, and Val;

(c) when the substitution occurs at position 72, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Glu, Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Gln, Ser, Thr, Trp, andTyr;

(d) when the substitution occurs at position 73, the substituting aminoacid is selected from the group consisting of Arg, Asn, Asp, Cys, Glu,Gly, Phe, His, Ile, Lys, Met, Pro, Ser, Thr, Trp, Tyr, and Val;

(e) when the substitution occurs at position 74, the substituting aminoacid is selected from the group consisting of Arg, Asn, Asp, Cys, Glu,Gly, Phe, His, Ile, Lys, Leu, Met, Gln, Ser, Thr, Trp, Tyr, and Val;

(f) when the substitution occurs at position 75, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Glu, Gly, Phe, His, Ile, Lys, Met, Gln, Ser, Thr, Trp, Tyr, and Val;

(g) when the substitution occurs at position 76, the substituting aminoacid is selected from the group consisting of Ala, Arg, Cys, Ile, Leu,Met, Gln, Ser, Thr, Trp, Tyr, and Val;

(h) when the substitution occurs at position 77, the substituting aminoacid is selected from the group consisting of Ala, Arg, Cys, Glu, Gly,Phe, His, Ile, Lys, Leu, Met, Pro, Gin, Ser, Thr, Trp, Tyr, and Val;

(i) when the substitution occurs at position 78, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Cys, Glu,Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Gin, Thr, Trp, Tyr, and Val;

(j) when the substitution occurs at position 79, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Cys, Gly,Phe, His, Lys, Leu, Met, Pro, Gin, Ser, Thr, Trp, Tyr, and Val;

(k) when the substitution occurs at position 80, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Glu, Phe, His, Lys, Leu, Met, Pro, Gin, Ser, Thr, Trp, Tyr, and Val;

(l) when the substitution occurs at position 81, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Glu, Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Gin, Ser, Thr, Trp, andTyr;

(m) when the substitution occurs at position 82, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Glu, Gly, Phe, His, Ile, Lys, Met, Pro, Gin, Ser, Thr, Trp, Tyr, andVal;

(n) when the substitution occurs at position 83, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Glu, Phe, His, Ile, Lys, Leu, Met, Pro, Gin, Ser, Thr, Trp, Tyr, andVal; and

(o) when the substitution occurs at position 84, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Glu, Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Gin, Ser, Thr, Trp, andTyr.

Wherein the variant has a modified amino acid sequence of a wild-typeamino acid sequence comprising a substitution at two or more positionscorresponding to positions 70-84 of BPN′:

(a) when a substitution occurs at position 70, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Gin, Glu, Phe, His, Ile, Lys, Leu, Met, Pro, Ser, Thr, Trp, Tyr, andVal;

(b) when a substitution occurs at position 71, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Gln, Glu, Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Ser, Trp, Tyr, andVal;

(c) when a substitution occurs at position 72, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Gin, Glu, Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Ser, Thr, Trp, andTyr;

(d) when a substitution occurs at position 73, the substituting aminoacid is selected from the group consisting of Arg, Asn, Asp, Cys, GlnGlu, Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Ser, Thr, Trp, Tyr, andVal;

(e) when a substitution occurs at position 74, the substituting aminoacid is selected from the group consisting of Arg, Asn, Asp, Cys, GlnGlu, Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Ser, Thr, Trp, Tyr, andVal;

(f) when a substitution occurs at position 75, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Gln Glu, Gly, Phe, His, Ile, Lys, Met, Pro, Ser, Thr, Trp, Tyr, and Val;

(g) when a substitution occurs at position 76, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asp, Cys, GlnGlu, Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Ser, Thr, Trp, Tyr, andVal;

(h) when a substitution occurs at position 77, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asp, Cys, GlnGlu, Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Ser, Thr, Trp, Tyr, andVal;

(i) when a substitution occurs at position 78, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Gln Glu, Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Thr, Trp, Tyr, and Val;

(j) when a substitution occurs at position 79, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Gln Glu, Gly, Phe, His, Lys, Leu, Met, Pro, Ser, Thr, Trp, Tyr, and Val;

(k) when a substitution occurs at position 80, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Gln Glu, Phe, His, Ile, Lys, Leu, Met, Pro, Ser, Thr, Trp, Tyr, and Val;

(l) when a substitution occurs at position 81, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Gln Glu, Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Ser, Thr, Trp, and Tyr;

(m) when a substitution occurs at position 82, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Gln Glu, Gly, Phe, His, Ile, Lys, Met, Pro, Ser, Thr, Trp, Tyr, and Val;

(n) when a substitution occurs at position 83, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Gln Glu, Phe, His, Ile, Lys, Leu, Met, Pro, Ser, Thr, Trp, Tyr, and Val;and

(o) when a substitution occurs at position 84, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Asp, Cys,Gln Glu, Gly, Phe, His, Ile, Lys, Leu, Met, Pro, Ser, Thr, Trp, and Tyr;

wherein the variant is not Asn76Asp+Asn77Asp; Asn76Asp+Ile79Glu; orAsn76Asp+Ser78Asp.

Even more preferably, the variants of the present invention comprise adeletion of one or more of positions 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83 (73-83), even more preferably one or more of 75, 76, 77, 78, 79,80, 81, 82 (75-82).

Tables 2-7 below exemplify non-limiting preferred variants of thepresent invention. With respect to these tables, in describing thespecific substitutions, the wild-type amino acid residue is given first,the corresponding position number is given second, and the substitutingamino acid is given third. Tables 3-7 delineate preferred variantshaving two or more substitutions. To illustrate, the first example ofTable 3 reads “VAL 81 THR LEU 82 PHE”. This example is meant toexemplify the variant Val81Thr+Leu82Phe.

Using similar notation, Tables 8-13 exemplify even more preferredvariants of the present invention.

TABLE 2 Single Substitution Variants GLY 83 VAL LEU 82 PHE LEU 82 HISLEU 82 TYR LEU 82 ALA VAL 81 THR VAL 81 ALA GLY 80 VAL ILE 79 LEU ILE 79MET ILE 79 THR ILE 79 VAL ILE 79 ALA SER 78 ASN SER 78 THR SER 78 ARGSER 78 GLN SER 78 HIS SER 78 LYS SER 78 TYR SER 78 ALA ASN 77 ALA ASN 76ALA LEU 75 ILE LEU 75 MET LEU 75 VAL LEU 75 ALA ALA 74 VAL ALA 73 VALVAL 72 ALA THR 71 ALA GLY 70 VAL

TABLE 3 Double Substitution Variants VAL 81 THR LEU 82 PHE VAL 81 THRLEU 82 HIS VAL 81 THR LEU 82 TYR ILE 79 LEU LEU 82 PHE ILE 79 LEU LEU 82HIS ILE 79 LEU LEU 82 TYR ILE 79 MET LEU 82 PHE ILE 79 MET LEU 82 HISILE 79 MET LEU 82 TYR ILE 79 THR LEU 82 PHE ILE 79 THR LEU 82 HIS ILE 79THR LEU 82 TYR ILE 79 VAL LEU 82 PHE ILE 79 VAL LEU 82 HIS ILE 79 VALLEU 82 TYR ILE 79 LEU VAL 81 THR ILE 79 MET VAL 81 THR ILE 79 THR VAL 81THR ILE 79 VAL VAL 81 THR SER 78 ASN LEU 82 PHE SER 78 ASN LEU 82 HISSER 78 ASN LEU 82 TYR SER 78 THR LEU 82 PHE SER 78 THR LEU 82 HIS SER 78THR LEU 82 TYR SER 78 ARG LEU 82 PHE SER 78 ARG LEU 82 HIS SER 78 ARGLEU 82 TYR SER 78 ASP LEU 82 PHE SER 78 ASP LEU 82 HIS SER 78 ASP LEU 82TYR SER 78 GLN LEU 82 PHE SER 78 GLN LEU 82 HIS SER 78 GLN LEU 82 TYRSER 78 HIS LEU 82 PHE SER 78 HIS LEU 82 HIS SER 78 HIS LEU 82 TYR SER 78LYS LEU 82 PHE SER 78 LYS LEU 82 HIS SER 78 LYS LEU 82 TYR SER 78 TYRLEU 82 PHE SER 78 TYR LEU 82 HIS SER 78 TYR LEU 82 TYR SER 78 ASN VAL 81THR SER 78 THR VAL 81 THR SER 78 ARG VAL 81 THR SER 78 ASP VAL 81 THRSER 78 GLN VAL 81 THR SER 78 HIS VAL 81 THR SER 78 LYS VAL 81 THR SER 78TYR VAL 81 THR SER 78 ASN ILE 79 LEU SER 78 ASN ILE 79 MET SER 78 ASNILE 79 THR SER 78 ASN ILE 79 VAL SER 78 THR ILE 79 LEU SER 78 THR ILE 79MET SER 78 THR ILE 79 THR SER 78 THR ILE 79 VAL SER 78 ARG ILE 79 LEUSER 78 ARG ILE 79 MET SER 78 ARG ILE 79 THR SER 78 ARG ILE 79 VAL SER 78ASP ILE 79 LEU SER 78 ASP ILE 79 MET SER 78 ASP ILE 79 THR SER 78 ASPILE 79 VAL SER 78 GLN ILE 79 LEU SER 78 GLN ILE 79 MET SER 78 GLN ILE 79THR SER 78 GLN ILE 79 VAL SER 78 HIS ILE 79 LEU SER 78 HIS ILE 79 METSER 78 HIS ILE 79 THR SER 78 HIS ILE 79 VAL SER 78 LYS ILE 79 LEU SER 78LYS ILE 79 MET SER 78 LYS ILE 79 THR SER 78 LYS ILE 79 VAL SER 78 TYRILE 79 LEU SER 78 TYR ILE 79 MET SER 78 TYR ILE 79 THR SER 78 TYR ILE 79VAL ASN 76 HIS LEU 82 PHE ASN 76 HIS LEU 82 HIS ASN 76 HIS LEU 82 TYRASN 76 HIS VAL 81 THR ASN 76 HIS ILE 79 LEU ASN 76 HIS ILE 79 MET ASN 76HIS ILE 79 THR ASN 76 HIS ILE 79 VAL ASN 76 HIS SER 78 ASN ASN 76 HISSER 78 THR ASN 76 HIS SER 78 ARG ASN 76 HIS SER 78 ASP ASN 76 HIS SER 78GLN ASN 76 HIS SER 78 HIS ASN 76 HIS SER 78 LYS ASN 76 HIS SER 78 TYRLEU 75 ILE LEU 82 PHE LEU 75 ILE LEU 82 HIS LEU 75 ILE LEU 82 TYR LEU 75MET LEU 82 PHE LEU 75 MET LEU 82 HIS LEU 75 MET LEU 82 TYR LEU 75 VALLEU 82 PHE LEU 75 VAL LEU 82 HIS LEU 75 VAL LEU 82 TYR LEU 75 ILE VAL 81THR LEU 75 MET VAL 81 THR LEU 75 VAL VAL 81 THR LEU 75 ILE ILE 79 LEULEU 75 ILE ILE 79 MET LEU 75 ILE ILE 79 THR LEU 75 ILE ILE 79 VAL LEU 75MET ILE 79 LEU LEU 75 MET ILE 79 MET LEU 75 MET ILE 79 THR LEU 75 METILE 79 VAL LEU 75 VAL ILE 79 LEU LEU 75 VAL ILE 79 MET LEU 75 VAL ILE 79THR LEU 75 VAL ILE 79 VAL LEU 75 ILE SER 78 ASN LEU 75 ILE SER 78 THRLEU 75 ILE SER 78 ARG LEU 75 ILE SER 78 ASP LEU 75 ILE SER 78 GLN LEU 75ILE SER 78 HIS LEU 75 ILE SER 78 LYS LEU 75 ILE SER 78 TYR LEU 75 METSER 78 ASN LEU 75 MET SER 78 THR LEU 75 MET SER 78 ARG LEU 75 MET SER 78ASP LEU 75 MET SER 78 GLN LEU 75 MET SER 78 HIS LEU 75 MET SER 78 LYSLEU 75 MET SER 78 TYR LEU 75 VAL SER 78 ASN LEU 75 VAL SER 78 THR LEU 75VAL SER 78 ARG LEU 75 VAL SER 78 ASP LEU 75 VAL SER 78 GLN LEU 75 VALSER 78 HIS LEU 75 VAL SER 78 LYS LEU 75 VAL SER 78 TYR LEU 75 ILE ASN 76HIS LEU 75 MET ASN 76 HIS LEU 75 VAL ASN 76 HIS

TABLE 4 Triple Substitution Variants ILE 79 LEU VAL 81 THR LEU 82 PHEILE 79 LEU VAL 81 THR LEU 82 HIS ILE 79 LEU VAL 81 THR LEU 82 TYR ILE 79MET VAL 81 THR LEU 82 PHE ILE 79 MET VAL 81 THR LEU 82 HIS ILE 79 METVAL 81 THR LEU 82 TYR ILE 79 THR VAL 81 THR LEU 82 PHE ILE 79 THR VAL 81THR LEU 82 HIS ILE 79 THR VAL 81 THR LEU 82 TYR ILE 79 VAL VAL 81 THRLEU 82 PHE ILE 79 VAL VAL 81 THR LEU 82 HIS ILE 79 VAL VAL 81 THR LEU 82TYR SER 78 ASN VAL 81 THR LEU 82 PHE SER 78 ASN VAL 81 THR LEU 82 HISSER 78 ASN VAL 81 THR LEU 82 TYR SER 78 THR VAL 81 THR LEU 82 PHE SER 78THR VAL 81 THR LEU 82 HIS SER 78 THR VAL 81 THR LEU 82 TYR SER 78 ARGVAL 81 THR LEU 82 PHE SER 78 ARG VAL 81 THR LEU 82 HIS SER 78 ARG VAL 81THR LEU 82 TYR SER 78 ASP VAL 81 THR LEU 82 PHE SER 78 ASP VAL 81 THRLEU 82 HIS SER 78 ASP VAL 81 THR LEU 82 TYR SER 78 GLN VAL 81 THR LEU 82PHE SER 78 GLN VAL 81 THR LEU 82 HIS SER 78 GLN VAL 81 THR LEU 82 TYRSER 78 HIS VAL 81 THR LEU 82 PHE SER 78 HIS VAL 81 THR LEU 82 HIS SER 78HIS VAL 81 THR LEU 82 TYR SER 78 LYS VAL 81 THR LEU 82 PHE SER 78 LYSVAL 81 THR LEU 82 HIS SER 78 LYS VAL 81 THR LEU 82 TYR SER 78 TYR VAL 81THR LEU 82 PHE SER 78 TYR VAL 81 THR LEU 82 HIS SER 78 TYR VAL 81 THRLEU 82 TYR SER 78 ASN ILE 79 LEU LEU 82 PHE SER 78 ASN ILE 79 LEU LEU 82HIS SER 78 ASN ILE 79 LEU LEU 82 TYR SER 78 ASN ILE 79 MET LEU 82 PHESER 78 ASN ILE 79 MET LEU 82 HIS SER 78 ASN ILE 79 MET LEU 82 TYR SER 78ASN ILE 79 THR LEU 82 PHE SER 78 ASN ILE 79 THR LEU 82 HIS SER 78 ASNILE 79 THR LEU 82 TYR SER 78 ASN ILE 79 VAL LEU 82 PHE SER 78 ASN ILE 79VAL LEU 82 HIS SER 78 ASN ILE 79 VAL LEU 82 TYR SER 78 THR ILE 79 LEULEU 82 PHE SER 78 THR ILE 79 LEU LEU 82 HIS SER 78 THR ILE 79 LEU LEU 82TYR SER 78 THR ILE 79 MET LEU 82 PHE SER 78 THR ILE 79 MET LEU 82 HISSER 78 THR ILE 79 MET LEU 82 TYR SER 78 THR ILE 79 THR LEU 82 PHE SER 78THR ILE 79 THR LEU 82 HIS SER 78 THR ILE 79 THR LEU 82 TYR SER 78 THRILE 79 VAL LEU 82 PHE SER 78 THR ILE 79 VAL LEU 82 HIS SER 78 THR ILE 79VAL LEU 82 TYR SER 78 ARG ILE 79 LEU LEU 82 PHE SER 78 ARG ILE 79 LEULEU 82 HIS SER 78 ARG ILE 79 LEU LEU 82 TYR SER 78 ARG ILE 79 MET LEU 82PHE SER 78 ARG ILE 79 MET LEU 82 HIS SER 78 ARG ILE 79 MET LEU 82 TYRSER 78 ARG ILE 79 THR LEU 82 PHE SER 78 ARG ILE 79 THR LEU 82 HIS SER 78ARG ILE 79 THR LEU 82 TYR SER 78 ARG ILE 79 VAL LEU 82 PHE SER 78 ARGILE 79 VAL LEU 82 HIS SER 78 ARG ILE 79 VAL LEU 82 TYR SER 78 ASP ILE 79LEU LEU 82 PHE SER 78 ASP ILE 79 LEU LEU 82 HIS SER 78 ASP ILE 79 LEULEU 82 TYR SER 78 ASP ILE 79 MET LEU 82 PHE SER 78 ASP ILE 79 MET LEU 82HIS SER 78 ASP ILE 79 MET LEU 82 TYR SER 78 ASP ILE 79 THR LEU 82 PHESER 78 ASP ILE 79 THR LEU 82 HIS SER 78 ASP ILE 79 THR LEU 82 TYR SER 78ASP ILE 79 VAL LEU 82 PHE SER 78 ASP ILE 79 VAL LEU 82 HIS SER 78 ASPILE 79 VAL LEU 82 TYR SER 78 GLN ILE 79 LEU LEU 82 PHE SER 78 GLN ILE 79LEU LEU 82 HIS SER 78 GLN ILE 79 LEU LEU 82 TYR SER 78 GLN ILE 79 METLEU 82 PRE SER 78 GLN ILE 79 MET LEU 82 HIS SER 78 GLN ILE 79 MET LEU 82TYR SER 78 GLN ILE 79 THR LEU 82 PHE SER 78 GLN ILE 79 THR LEU 82 HISSER 78 GLN ILE 79 THR LEU 82 TYR SER 78 GLN ILE 79 VAL LEU 82 PHE SER 78GLN ILE 79 VAL LEU 82 HIS SER 78 GLN ILE 79 VAL LEU 82 TYR SER 78 HISILE 79 LEU LEU 82 PHE SER 78 HIS ILE 79 LEU LEU 82 HIS SER 78 HIS ILE 79LEU LEU 82 TYR SER 78 HIS ILE 79 MET LEU 82 PHE SER 78 HIS ILE 79 METLEU 82 HIS SER 78 HIS ILE 79 MET LEU 82 TYR SER 78 HIS ILE 79 THR LEU 82PHE SER 78 HIS ILE 79 THR LEU 82 HIS SER 78 HIS ILE 79 THR LEU 82 TYRSER 78 HIS ILE 79 VAL LEU 82 PHE SER 78 HIS ILE 79 VAL LEU 82 HIS SER 78HIS ILE 79 VAL LEU 82 TYR SER 78 LYS ILE 79 LEU LEU 82 PHE SER 78 LYSILE 79 LEU LEU 82 HIS SER 78 LYS ILE 79 LEU LEU 82 TYR SER 78 LYS ILE 79MET LEU 82 PHE SER 78 LYS ILE 79 MET LEU 82 HIS SER 78 LYS ILE 79 METLEU 82 TYR SER 78 LYS ILE 79 THR LEU 82 PHE SER 78 LYS ILE 79 THR LEU 82HIS SER 78 LYS ILE 79 THR LEU 82 TYR SER 78 LYS ILE 79 VAL LEU 82 PRESER 78 LYS ILE 79 VAL LEU 82 HIS SER 78 LYS ILE 79 VAL LEU 82 TYR SER 78TYR ILE 79 LEU LEU 82 PRE SER 78 TYR ILE 79 LEU LEU 82 HIS SER 78 TYRILE 79 LEU LEU 82 TYR SER 78 TYR ILE 79 MET LEU 82 PHE SER 78 TYR ILE 79MET LEU 82 HIS SER 78 TYR ILE 79 MET LEU 82 TYR SER 78 TYR ILE 79 THRLEU 82 PHE SER 78 TYR ILE 79 THR LEU 82 HIS SER 78 TYR ILE 79 THR LEU 82TYR SER 78 TYR ILE 79 VAL LEU 82 PRE SER 78 TYR ILE 79 VAL LEU 82 HISSER 78 TYR ILE 79 VAL LEU 82 TYR SER 78 ASN ILE 79 LEU VAL 81 THR SER 78ASN ILE 79 MET VAL 81 THR SER 78 ASN ILE 79 THR VAL 81 THR SER 78 ASNILE 79 VAL VAL 81 THR SER 78 THR ILE 79 LEU VAL 81 THR SER 78 THR ILE 79MET VAL 81 THR SER 78 THR ILE 79 THR VAL 81 THR SER 78 THR ILE 79 VALVAL 81 THR SER 78 GLN ILE 79 LEU LEU 82 PHE SER 78 GLN ILE 79 LEU LEU 82HIS SER 78 GLN ILE 79 LEU LEU 82 TYR SER 78 GLN ILE 79 MET LEU 82 PRESER 78 GLN ILE 79 MET LEU 82 HIS SER 78 GLN ILE 79 MET LEU 82 TYR SER 78GLN ILE 79 THR LEU 82 PHE SER 78 GLN ILE 79 THR LEU 82 HIS SER 78 GLNILE 79 THR LEU 82 TYR SER 78 GLN ILE 79 VAL LEU 82 PHE SER 78 GLN ILE 79VAL LEU 82 HIS SER 78 GLN ILE 79 VAL LEU 82 TYR SER 78 HIS ILE 79 LEULEU 82 PHE SER 78 HIS ILE 79 LEU LEU 82 HIS SER 78 HIS ILE 79 LEU LEU 82TYR SER 78 HIS ILE 79 MET LEU 82 PHE SER 78 HIS ILE 79 MET LEU 82 HISSER 78 HIS ILE 79 MET LEU 82 TYR SER 78 HIS ILE 79 THR LEU 82 PHE SER 78HIS ILE 79 THR LEU 82 HIS SER 78 HIS ILE 79 THR LEU 82 TYR SER 78 HISILE 79 VAL LEU 82 PHE SER 78 HIS ILE 79 VAL LEU 82 HIS SER 78 HIS ILE 79VAL LEU 82 TYR SER 78 LYS ILE 79 LEU LEU 82 PHE SER 78 LYS ILE 79 LEULEU 82 HIS SER 78 LYS ILE 79 LEU LEU 82 TYR SER 78 LYS ILE 79 MET LEU 82PHE SER 78 LYS ILE 79 MET LEU 82 HIS SER 78 LYS ILE 79 MET LEU 82 TYRSER 78 LYS ILE 79 THR LEU 82 PHE SER 78 LYS ILE 79 THR LEU 82 HIS SER 78LYS ILE 79 THR LEU 82 TYR SER 78 LYS ILE 79 VAL LEU 82 PRE SER 78 LYSILE 79 VAL LEU 82 HIS SER 78 LYS ILE 79 VAL LEU 82 TYR SER 78 TYR ILE 79LEU LEU 82 PRE SER 78 TYR ILE 79 LEU LEU 82 HIS SER 78 TYR ILE 79 LEULEU 82 TYR SER 78 TYR ILE 79 MET LEU 82 PHE SER 78 TYR ILE 79 MET LEU 82HIS SER 78 TYR ILE 79 MET LEU 82 TYR SER 78 TYR ILE 79 THR LEU 82 PHESER 78 TYR ILE 79 THR LEU 82 HIS SER 78 TYR ILE 79 THR LEU 82 TYR SER 78TYR ILE 79 VAL LEU 82 PRE SER 78 TYR ILE 79 VAL LEU 82 HIS SER 78 TYRILE 79 VAL LEU 82 TYR SER 78 ASN ILE 79 LEU VAL 81 THR SER 78 ASN ILE 79MET VAL 81 THR SER 78 ASN ILE 79 THR VAL 81 THR SER 78 ASN ILE 79 VALVAL 81 THR SER 78 THR ILE 79 LEU VAL 81 THR SER 78 THR ILE 79 MET VAL 81THR SER 78 THR ILE 79 THR VAL 81 THR SER 78 THR ILE 79 VAL VAL 81 THRSER 78 ARG ILE 79 LEU VAL 81 THR SER 78 ARG ILE 79 MET VAL 81 THR SER 78ARG ILE 79 THR VAL 81 THR SER 78 ARG ILE 79 VAL VAL 81 THR SER 78 ASPILE 79 LEU VAL 81 THR SER 78 ASP ILE 79 MET VAL 81 THR SER 78 ASP ILE 79THR VAL 81 THR SER 78 ASP ILE 79 VAL VAL 81 THR SER 78 GLN ILE 79 LEUVAL 81 THR SER 78 GLN ILE 79 MET VAL 81 THR SER 78 GLN ILE 79 THR VAL 81THR SER 78 GLN ILE 79 VAL VAL 81 THR SER 78 HIS ILE 79 LEU VAL 81 THRSER 78 HIS ILE 79 MET VAL 81 THR SER 78 HIS ILE 79 THR VAL 81 THR SER 78HIS ILE 79 VAL VAL 81 THR SER 78 LYS ILE 79 LEU VAL 81 THR SER 78 LYSILE 79 MET VAL 81 THR SER 78 LYS ILE 79 THR VAL 81 THR SER 78 LYS ILE 79VAL VAL 81 THR SER 78 TYR ILE 79 LEU VAL 81 THR SER 78 TYR ILE 79 METVAL 81 THR SER 78 TYR ILE 79 THR VAL 81 THR SER 78 TYR ILE 79 VAL VAL 81THR ASN 76 HIS VAL 81 THR LEU 82 PHE ASN 76 HIS VAL 81 THR LEU 82 HISASN 76 HIS VAL 81 THR LEU 82 TYR ASN 76 HIS ILE 79 LEU LEU 82 PHE ASN 76HIS ILE 79 LEU LEU 82 HIS ASN 76 HIS ILE 79 LEU LEU 82 TYR ASN 76 HISILE 79 MET LEU 82 PHE ASN 76 HIS ILE 79 MET LEU 82 HIS ASN 76 HIS ILE 79MET LEU 82 TYR ASN 76 HIS ILE 79 THR LEU 82 PHE ASN 76 HIS ILE 79 THRLEU 82 HIS ASN 76 HIS ILE 79 THR LEU 82 TYR ASN 76 HIS ILE 79 VAL LEU 82PHE ASN 76 HIS ILE 79 VAL LEU 82 HIS ASN 76 HIS ILE 79 VAL LEU 82 TYRASN 76 HIS ILE 79 LEU VAL 81 THR ASN 76 HIS ILE 79 MET VAL 81 THR ASN 76HIS ILE 79 THR VAL 81 THR ASN 76 HIS ILE 79 VAL VAL 81 THR ASN 76 HISSER 78 ASN LEU 82 PHE ASN 76 HIS SER 78 ASN LEU 82 HIS ASN 76 HIS SER 78ASN LEU 82 TYR ASN 76 HIS SER 78 THR LEU 82 PHE ASN 76 HIS SER 78 THRLEU 82 HIS ASN 76 HIS SER 78 THR LEU 82 TYR ASN 76 HIS SER 78 ARG LEU 82PHE ASN 76 HIS SER 78 ARG LEU 82 HIS ASN 76 HIS SER 78 ARG LEU 82 TYRASN 76 HIS SER 78 ASP LEU 82 PHE ASN 76 HIS SER 78 ASP LEU 82 HIS ASN 76HIS SER 78 ASP LEU 82 TYR ASN 76 HIS SER 78 GLN LEU 82 PHE ASN 76 HISSER 78 GLN LEU 82 HIS ASN 76 HIS SER 78 GLN LEU 82 TYR ASN 76 HIS SER 78HIS LEU 82 PHE ASN 76 HIS SER 78 HIS LEU 82 HIS ASN 76 HIS SER 78 HISLEU 82 TYR ASN 76 HIS SER 78 LYS LEU 82 PHE ASN 76 HIS SER 78 LYS LEU 82HIS ASN 76 HIS SER 78 LYS LEU 82 TYR ASN 76 HIS SER 78 TYR LEU 82 PHEASN 76 HIS SER 78 TYR LEU 82 HIS ASN 76 HIS SER 78 TYR LEU 82 TYR ASN 76HIS SER 78 ASN VAL 81 THR ASN 76 HIS SER 78 THR VAL 81 THR ASN 76 HISSER 78 ARG VAL 81 THR ASN 76 HIS SER 78 ASP VAL 81 THR ASN 76 HIS SER 78GLN VAL 81 THR ASN 76 HIS SER 78 HIS VAL 81 THR ASN 76 HIS SER 78 LYSVAL 81 THR ASN 76 HIS SER 78 TYR VAL 81 THR ASN 76 HIS SER 78 ASN ILE 79LEU ASN 76 HIS SER 78 ASN ILE 79 MET ASN 76 HIS SER 78 ASN ILE 79 THRASN 76 HIS SER 78 ASN ILE 79 VAL ASN 76 HIS SER 78 THR ILE 79 LEU ASN 76HIS SER 78 THR ILE 79 MET ASN 76 HIS SER 78 THR ILE 79 THR ASN 76 HISSER 78 THR ILE 79 VAL ASN 76 HIS SER 78 ARG ILE 79 LEU ASN 76 HIS SER 78ARG ILE 79 MET ASN 76 HIS SER 78 ARG ILE 79 THR ASN 76 HIS SER 78 ARGILE 79 VAL ASN 76 HIS SER 78 ASP ILE 79 LEU ASN 76 HIS SER 78 ASP ILE 79MET ASN 76 HIS SER 78 ASP ILE 79 THR ASN 76 HIS SER 78 ASP ILE 79 VALASN 76 HIS SER 78 GLN ILE 79 LEU ASN 76 HIS SER 78 GLN ILE 79 MET ASN 76HIS SER 78 GLN ILE 79 THR ASN 76 HIS SER 78 GLN ILE 79 VAL ASN 76 HISSER 78 HIS ILE 79 LEU ASN 76 HIS SER 78 HIS ILE 79 MET ASN 76 HIS SER 78HIS ILE 79 THR ASN 76 HIS SER 78 HIS ILE 79 VAL ASN 76 HIS SER 78 LYSILE 79 LEU ASN 76 HIS SER 78 LYS ILE 79 MET ASN 76 HIS SER 78 LYS ILE 79THR ASN 76 HIS SER 78 LYS ILE 79 VAL ASN 76 HIS SER 78 TYR ILE 79 LEUASN 76 HIS SER 78 TYR ILE 79 MET ASN 76 HIS SER 78 TYR ILE 79 THR ASN 76HIS SER 78 TYR ILE 79 VAL LEU 75 ILE VAL 81 THR LEU 82 PHE LEU 75 ILEVAL 81 THR LEU 82 HIS LEU 75 ILE VAL 81 THR LEU 82 TYR LEU 75 MET VAL 81THR LEU 82 PHE LEU 75 MET VAL 81 THR LEU 82 HIS LEU 75 MET VAL 81 THRLEU 82 TYR LEU 75 VAL VAL 81 THR LEU 82 PHE LEU 75 VAL VAL 81 THR LEU 82HIS LEU 75 VAL VAL 81 THR LEU 82 TYR LEU 75 ILE ILE 79 LEU LEU 82 PHELEU 75 ILE ILE 79 LEU LEU 82 HIS LEU 75 ILE ILE 79 LEU LEU 82 TYR LEU 75ILE ILE 79 MET LEU 82 PHE LEU 75 ILE ILE 79 MET LEU 82 HIS LEU 75 ILEILE 79 MET LEU 82 TYR LEU 75 ILE ILE 79 THR LEU 82 PHE LEU 75 ILE ILE 79THR LEU 82 HIS LEU 75 ILE ILE 79 THR LEU 82 TYR LEU 75 ILE ILE 79 VALLEU 82 PHE LEU 75 ILE ILE 79 VAL LEU 82 HIS LEU 75 ILE ILE 79 VAL LEU 82TYR LEU 75 MET ILE 79 LEU LEU 82 PHE LEU 75 MET ILE 79 LEU LEU 82 HISLEU 75 MET ILE 79 LEU LEU 82 TYR LEU 75 MET ILE 79 MET LEU 82 PHE LEU 75MET ILE 79 MET LEU 82 HIS LEU 75 MET ILE 79 MET LEU 82 TYR LEU 75 METILE 79 THR LEU 82 PHE LEU 75 MET ILE 79 THR LEU 82 HIS LEU 75 MET ILE 79THR LEU 82 TYR LEU 75 MET ILE 79 VAL LEU 82 PHE LEU 75 MET ILE 79 VALLEU 82 HIS LEU 75 MET ILE 79 VAL LEU 82 TYR LEU 75 VAL ILE 79 LEU LEU 82PHE LEU 75 VAL ILE 79 LEU LEU 82 HIS LEU 75 VAL ILE 79 LEU LEU 82 TYRLEU 75 VAL ILE 79 MET LEU 82 PHE LEU 75 VAL ILE 79 MET LEU 82 HIS LEU 75VAL ILE 79 MET LEU 82 TYR LEU 75 VAL ILE 79 THR LEU 82 PHE LEU 75 VALILE 79 THR LEU 82 HIS LEU 75 VAL ILE 79 THR LEU 82 TYR LEU 75 VAL ILE 79VAL LEU 82 PHE LEU 75 VAL ILE 79 VAL LEU 82 HIS LEU 75 VAL ILE 79 VALLEU 82 TYR LEU 75 ILE ILE 79 LEU VAL 81 THR LEU 75 ILE ILE 79 MET VAL 81THR LEU 75 ILE ILE 79 THR VAL 81 THR LEU 75 ILE ILE 79 VAL VAL 81 THRLEU 75 MET ILE 79 LEU VAL 81 THR LEU 75 MET ILE 79 MET VAL 81 THR LEU 75MET ILE 79 THR VAL 81 THR LEU 75 MET ILE 79 VAL VAL 81 THR LEU 75 VALILE 79 LEU VAL 81 THR LEU 75 VAL ILE 79 MET VAL 81 THR LEU 75 VAL ILE 79THR VAL 81 THR LEU 75 VAL ILE 79 VAL VAL 81 THR LEU 75 ILE SER 78 ASNLEU 82 PHE LEU 75 ILE SER 78 ASN LEU 82 HIS LEU 75 ILE SER 78 ASN LEU 82TYR LEU 75 ILE SER 78 THR LEU 82 PHE LEU 75 ILE SER 78 THR LEU 82 HISLEU 75 ILE SER 78 THR LEU 82 TYR LEU 75 ILE SER 78 ARG LEU 82 PHE LEU 75ILE SER 78 ARG LEU 82 HIS LEU 75 ILE SER 78 ARG LEU 82 TYR LEU 75 ILESER 78 ASP LEU 82 PHE LEU 75 ILE SER 78 ASP LEU 82 HIS LEU 75 ILE SER 78ASP LEU 82 TYR LEU 75 ILE SER 78 GLN LEU 82 PHE LEU 75 ILE SER 78 GLNLEU 82 HIS LEU 75 ILE SER 78 GLN LEU 82 TYR LEU 75 ILE SER 78 HIS LEU 82PHE LEU 75 ILE SER 78 HIS LEU 82 HIS LEU 75 ILE SER 78 HIS LEU 82 TYRLEU 75 ILE SER 78 LYS LEU 82 PHE LEU 75 ILE SER 78 LYS LEU 82 HIS LEU 75ILE SER 78 LYS LEU 82 TYR LEU 75 ILE SER 78 TYR LEU 82 PHE LEU 75 ILESER 78 TYR LEU 82 HIS LEU 75 ILE SER 78 TYR LEU 82 TYR LEU 75 MET SER 78ASN LEU 82 PHE LEU 75 MET SER 78 ASN LEU 82 HIS LEU 75 MET SER 78 ASNLEU 82 TYR LEU 75 MET SER 78 THR LEU 82 PHE LEU 75 MET SER 78 THR LEU 82HIS LEU 75 MET SER 78 THR LEU 82 TYR LEU 75 MET SER 78 ARG LEU 82 PHELEU 75 MET SER 78 ARG LEU 82 HIS LEU 75 MET SER 78 ARG LEU 82 TYR LEU 75MET SER 78 ASP LEU 82 PHE LEU 75 MET SER 78 ASP LEU 82 HIS LEU 75 METSER 78 ASP LEU 82 TYR LEU 75 MET SER 78 GLN LEU 82 PHE LEU 75 MET SER 78GLN LEU 82 HIS LEU 75 MET SER 78 GLN LEU 82 TYR LEU 75 MET SER 78 HISLEU 82 PHE LEU 75 MET SER 78 HIS LEU 82 HIS LEU 75 MET SER 78 HIS LEU 82TYR LEU 75 MET SER 78 LYS LEU 82 PHE LEU 75 MET SER 78 LYS LEU 82 HISLEU 75 MET SER 78 LYS LEU 82 TYR LEU 75 MET SER 78 TYR LEU 82 PHE LEU 75MET SER 78 TYR LEU 82 HIS LEU 75 MET SER 78 TYR LEU 82 TYR LEU 75 VALSER 78 ASN LEU 82 PHE LEU 75 VAL SER 78 ASN LEU 82 HIS LEU 75 VAL SER 78ASN LEU 82 TYR LEU 75 VAL SER 78 THR LEU 82 PHE LEU 75 VAL SER 78 THRLEU 82 HIS LEU 75 VAL SER 78 THR LEU 82 TYR LEU 75 VAL SER 78 ARG LEU 82PHE LEU 75 VAL SER 78 ARG LEU 82 HIS LEU 75 VAL SER 78 ARG LEU 82 TYRLEU 75 VAL SER 78 ASP LEU 82 PHE LEU 75 VAL SER 78 ASP LEU 82 HIS LEU 75VAL SER 78 ASP LEU 82 TYR LEU 75 VAL SER 78 GLN LEU 82 PHE LEU 75 VALSER 78 GLN LEU 82 HIS LEU 75 VAL SER 78 GLN LEU 82 TYR LEU 75 VAL SER 78HIS LEU 82 PHE LEU 75 VAL SER 78 HIS LEU 82 HIS LEU 75 VAL SER 78 HISLEU 82 TYR LEU 75 VAL SER 78 LYS LEU 82 PHE LEU 75 VAL SER 78 LYS LEU 82HIS LEU 75 VAL SER 78 LYS LEU 82 TYR LEU 75 VAL SER 78 TYR LEU 82 PHELEU 75 VAL SER 78 TYR LEU 82 HIS LEU 75 VAL SER 78 TYR LEU 82 TYR LEU 75ILE SER 78 ASN VAL 81 THR LEU 75 ILE SER 78 THR VAL 81 THR LEU 75 ILESER 78 ARG VAL 81 THR LEU 75 ILE SER 78 ASP VAL 81 THR LEU 75 ILE SER 78GLN VAL 81 THR LEU 75 ILE SER 78 HIS VAL 81 THR LEU 75 ILE SER 78 LYSVAL 81 THR LEU 75 ILE SER 78 TYR VAL 81 THR LEU 75 MET SER 78 ASN VAL 81THR LEU 75 MET SER 78 THR VAL 81 THR LEU 75 MET SER 78 ARG VAL 81 THRLEU 75 MET SER 78 ASP VAL 81 THR LEU 75 MET SER 78 GLN VAL 81 THR LEU 75MET SER 78 HIS VAL 81 THR LEU 75 MET SER 78 LYS VAL 81 THR LEU 75 METSER 78 TYR VAL 81 THR LEU 75 VAL SER 78 ASN VAL 81 THR LEU 75 VAL SER 78THR VAL 81 THR LEU 75 VAL SER 78 ARG VAL 81 THR LEU 75 VAL SER 78 ASPVAL 81 THR LEU 75 VAL SER 78 GLN VAL 81 THR LEU 75 VAL SER 78 HIS VAL 81THR LEU 75 VAL SER 78 LYS VAL 81 THR LEU 75 VAL SER 78 TYR VAL 81 THRLEU 75 ILE SER 78 ASN ILE 79 LEU LEU 75 ILE SER 78 ASN ILE 79 MET LEU 75ILE SER 78 ASN ILE 79 THR LEU 75 ILE SER 78 ASN ILE 79 VAL LEU 75 ILESER 78 THR ILE 79 LEU LEU 75 ILE SER 78 THR ILE 79 MET LEU 75 ILE SER 78THR ILE 79 THR LEU 75 ILE SER 78 THR ILE 79 VAL LEU 75 ILE SER 78 ARGILE 79 LEU LEU 75 ILE SER 78 ARG ILE 79 MET LEU 75 ILE SER 78 ARG ILE 79THR LEU 75 ILE SER 78 ARG ILE 79 VAL LEU 75 ILE SER 78 ASP ILE 79 LEULEU 75 ILE SER 78 ASP ILE 79 MET LEU 75 ILE SER 78 ASP ILE 79 THR LEU 75ILE SER 78 ASP ILE 79 VAL LEU 75 ILE SER 78 GLN ILE 79 LEU LEU 75 ILESER 78 GLN ILE 79 MET LEU 75 ILE SER 78 GLN ILE 79 THR LEU 75 ILE SER 78GLN ILE 79 VAL LEU 75 ILE SER 78 HIS ILE 79 LEU LEU 75 ILE SER 78 HISILE 79 MET LEU 75 ILE SER 78 HIS ILE 79 THR LEU 75 ILE SER 78 HIS ILE 79VAL LEU 75 ILE SER 78 LYS ILE 79 LEU LEU 75 ILE SER 78 LYS ILE 79 METLEU 75 ILE SER 78 LYS ILE 79 THR LEU 75 ILE SER 78 LYS ILE 79 VAL LEU 75ILE SER 78 TYR ILE 79 LEU LEU 75 ILE SER 78 TYR ILE 79 MET LEU 75 ILESER 78 TYR ILE 79 THR LEU 75 ILE SER 78 TYR ILE 79 VAL LEU 75 MET SER 78ASN ILE 79 LEU LEU 75 MET SER 78 ASN ILE 79 MET LEU 75 MET SER 78 ASNILE 79 THR LEU 75 MET SER 78 ASN ILE 79 VAL LEU 75 MET SER 78 THR ILE 79LEU LEU 75 MET SER 78 THR ILE 79 MET LEU 75 MET SER 78 THR ILE 79 THRLEU 75 MET SER 78 THR ILE 79 VAL LEU 75 MET SER 78 ARG ILE 79 LEU LEU 75MET SER 78 ARG ILE 79 MET LEU 75 MET SER 78 ARG ILE 79 THR LEU 75 METSER 78 ARG ILE 79 VAL LEU 75 MET SER 78 ASP ILE 79 LEU LEU 75 MET SER 78ASP ILE 79 MET LEU 75 MET SER 78 ASP ILE 79 THR LEU 75 MET SER 78 ASPILE 79 VAL LEU 75 MET SER 78 GLN ILE 79 LEU LEU 75 MET SER 78 GLN ILE 79MET LEU 75 MET SER 78 GLN ILE 79 THR LEU 75 MET SER 78 GLN ILE 79 VALLEU 75 MET SER 78 HIS ILE 79 LEU LEU 75 MET SER 78 HIS ILE 79 MET LEU 75MET SER 78 HIS ILE 79 THR LEU 75 MET SER 78 HIS ILE 79 VAL LEU 75 METSER 78 LYS ILE 79 LEU LEU 75 MET SER 78 LYS ILE 79 MET LEU 75 MET SER 78LYS ILE 79 THR LEU 75 MET SER 78 LYS ILE 79 VAL LEU 75 MET SER 78 TYRILE 79 LEU LEU 75 MET SER 78 TYR ILE 79 MET LEU 75 MET SER 78 TYR ILE 79THR LEU 75 MET SER 78 TYR ILE 79 VAL LEU 75 VAL SER 78 ASN ILE 79 LEULEU 75 VAL SER 78 ASN ILE 79 MET LEU 75 VAL SER 78 ASN ILE 79 THR LEU 75VAL SER 78 ASN ILE 79 VAL LEU 75 VAL SER 78 THR ILE 79 LEU LEU 75 VALSER 78 THR ILE 79 MET LEU 75 VAL SER 78 THR ILE 79 THR LEU 75 VAL SER 78THR ILE 79 VAL LEU 75 VAL SER 78 ARG ILE 79 LEU LEU 75 VAL SER 78 ARGILE 79 MET LEU 75 VAL SER 78 ARG ILE 79 THR LEU 75 VAL SER 78 ARG ILE 79VAL LEU 75 VAL SER 78 ASP ILE 79 LEU LEU 75 VAL SER 78 ASP ILE 79 METLEU 75 VAL SER 78 ASP ILE 79 THR LEU 75 VAL SER 78 ASP ILE 79 VAL LEU 75VAL SER 78 GLN ILE 79 LEU LEU 75 VAL SER 78 GLN ILE 79 MET LEU 75 VALSER 78 GLN ILE 79 THR LEU 75 VAL SER 78 GLN ILE 79 VAL LEU 75 VAL SER 78HIS ILE 79 LEU LEU 75 VAL SER 78 HIS ILE 79 MET LEU 75 VAL SER 78 HISILE 79 THR LEU 75 VAL SER 78 HIS ILE 79 VAL LEU 75 VAL SER 78 LYS ILE 79LEU LEU 75 VAL SER 78 LYS ILE 79 MET LEU 75 VAL SER 78 LYS ILE 79 THRLEU 75 VAL SER 78 LYS ILE 79 VAL LEU 75 VAL SER 78 TYR ILE 79 LEU LEU 75VAL SER 78 TYR ILE 79 MET LEU 75 VAL SER 78 TYR ILE 79 THR LEU 75 VALSER 78 TYR ILE 79 VAL LEU 75 ILE ASN 76 HIS LEU 82 PHE LEU 75 ILE ASN 76HIS LEU 82 HIS LEU 75 ILE ASN 76 HIS LEU 82 TYR LEU 75 MET ASN 76 HISLEU 82 PHE LEU 75 MET ASN 76 HIS LEU 82 HIS LEU 75 MET ASN 76 HIS LEU 82TYR LEU 75 VAL ASN 76 HIS LEU 82 PHE LEU 75 VAL ASN 76 HIS LEU 82 HISLEU 75 VAL ASN 76 HIS LEU 82 TYR LEU 75 ILE ASN 76 HIS VAL 81 THR LEU 75MET ASN 76 HIS VAL 81 THR LEU 75 VAL ASN 76 HIS VAL 81 THR LEU 75 ILEASN 76 HIS ILE 79 LEU LEU 75 ILE ASN 76 HIS ILE 79 MET LEU 75 ILE ASN 76HIS ILE 79 THR LEU 75 ILE ASN 76 HIS ILE 79 VAL LEU 75 MET ASN 76 HISILE 79 LEU LEU 75 MET ASN 76 HIS ILE 79 MET LEU 75 MET ASN 76 HIS ILE 79THR LEU 75 MET ASN 76 HIS ILE 79 VAL LEU 75 VAL ASN 76 HIS ILE 79 LEULEU 75 VAL ASN 76 HIS ILE 79 MET LEU 75 VAL ASN 76 HIS ILE 79 THR LEU 75VAL ASN 76 HIS ILE 79 VAL LEU 75 ILE ASN 76 HIS SER 78 ASN LEU 75 ILEASN 76 HIS SER 78 THR LEU 75 ILE ASN 76 HIS SER 78 ARG LEU 75 ILE ASN 76HIS SER 78 ASP LEU 75 ILE ASN 76 HIS SER 78 GLN LEU 75 ILE ASN 76 HISSER 78 HIS LEU 75 ILE ASN 76 HIS SER 78 LYS LEU 75 ILE ASN 76 HIS SER 78TYR LEU 75 MET ASN 76 HIS SER 78 ASN LEU 75 MET ASN 76 HIS SER 78 THRLEU 75 MET ASN 76 HIS SER 78 ARG LEU 75 MET ASN 76 HIS SER 78 ASP LEU 75MET ASN 76 HIS SER 78 GLN LEU 75 MET ASN 76 HIS SER 78 HIS LEU 75 METASN 76 HIS SER 78 LYS LEU 75 MET ASN 76 HIS SER 78 TYR LEU 75 VAL ASN 76HIS SER 78 ASN LEU 75 VAL ASN 76 HIS SER 78 THR LEU 75 VAL ASN 76 HISSER 78 ARG LEU 75 VAL ASN 76 HIS SER 78 ASP LEU 75 VAL ASN 76 HIS SER 78GLN LEU 75 VAL ASN 76 HIS SER 78 HIS LEU 75 VAL ASN 76 HIS SER 78 LYSLEU 75 VAL ASN 76 HIS SER 78 TYR

TABLE 5 Quadruple Substitution Variants SER 78 ASN ILE 79 LEU VAL 81 THRLEU 82 PHE SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 HIS SER 78 ASN ILE 79LEU VAL 81 THR LEU 82 TYR SER 78 ASN ILE 79 MET VAL 81 THR LEU 82 PHESER 78 ASN ILE 79 MET VAL 81 THR LEU 82 HIS SER 78 ASN ILE 79 MET VAL 81THR LEU 82 TYR SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 PHE SER 78 ASNILE 79 THR VAL 81 THR LEU 82 HIS SER 78 ASN ILE 79 THR VAL 81 THR LEU 82TYR SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 PHE SER 78 ASN ILE 79 VALVAL 81 THR LEU 82 HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 TYR SER 78THR ILE 79 LEU VAL 81 THR LEU 82 PHE SER 78 THR ILE 79 LEU VAL 81 THRLEU 82 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 TYR SER 78 THR ILE 79MET VAL 81 THR LEU 82 PHE SER 78 THR ILE 79 MET VAL 81 THR LEU 82 HISSER 78 THR ILE 79 MET VAL 81 THR LEU 82 TYR SER 78 THR ILE 79 THR VAL 81THR LEU 82 PHE SER 78 THR ILE 79 THR VAL 81 THR LEU 82 HIS SER 78 THRILE 79 THR VAL 81 THR LEU 82 TYR SER 78 THR ILE 79 VAL VAL 81 THR LEU 82PHE SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 HIS SER 78 THR ILE 79 VALVAL 81 THR LEU 82 TYR SER 78 ARG ILE 79 LEU VAL 81 THR LEU 82 PHE SER 78ARG ILE 79 LEU VAL 81 THR LEU 82 HIS SER 78 ARG ILE 79 LEU VAL 81 THRLEU 82 TYR SER 78 ARG ILE 79 MET VAL 81 THR LEU 82 PHE SER 78 ARG ILE 79MET VAL 81 THR LEU 82 HIS SER 78 ARG ILE 79 MET VAL 81 THR LEU 82 TYRSER 78 ARG ILE 79 THR VAL 81 THR LEU 82 PHE SER 78 ARG ILE 79 THR VAL 81THR LEU 82 HIS SER 78 ARG ILE 79 THR VAL 81 THR LEU 82 TYR SER 78 ARGILE 79 VAL VAL 81 THR LEU 82 PHE SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82HIS SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82 TYR SER 78 ASP ILE 79 LEUVAL 81 THR LEU 82 PHE SER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 HIS SER 78ASP ILE 79 LEU VAL 81 THR LEU 82 TYR SER 78 ASP ILE 79 MET VAL 81 THRLEU 82 PHE SER 78 ASP ILE 79 MET VAL 81 THR LEU 82 HIS SER 78 ASP ILE 79MET VAL 81 THR LEU 82 TYR SER 78 ASP ILE 79 THR VAL 81 THR LEU 82 PHESER 78 ASP ILE 79 THR VAL 81 THR LEU 82 HIS SER 78 ASP ILE 79 THR VAL 81THR LEU 82 TYR SER 78 ASP ILE 79 VAL VAL 81 THR LEU 82 PHE SER 78 ASPILE 79 VAL VAL 81 THR LEU 82 HIS SER 78 ASP ILE 79 VAL VAL 81 THR LEU 82TYR SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 PHE SER 78 GLN ILE 79 LEUVAL 81 THR LEU 82 HIS SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 TYR SER 78GLN ILE 79 MET VAL 81 THR LEU 82 PHE SER 78 GLN ILE 79 MET VAL 81 THRLEU 82 HIS SER 78 GLN ILE 79 MET VAL 81 THR LEU 82 TYR SER 78 GLN ILE 79THR VAL 81 THR LEU 82 PHE SER 78 GLN ILE 79 THR VAL 81 THR LEU 82 HISSER 78 GLN ILE 79 THR VAL 81 THR LEU 82 TYR SER 78 GLN ILE 79 VAL VAL 81THR LEU 82 PHE SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 HIS SER 78 GLNILE 79 VAL VAL 81 THR LEU 82 TYR SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82PHE SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 HIS SER 78 HIS ILE 79 LEUVAL 81 THR LEU 82 TYR SER 78 HIS ILE 79 MET VAL 81 THR LEU 82 PHE SER 78HIS ILE 79 MET VAL 81 THR LEU 82 HIS SER 78 HIS ILE 79 MET VAL 81 THRLEU 82 TYR SER 78 HIS ILE 79 THR VAL 81 THR LEU 82 PHE SER 78 HIS ILE 79THR VAL 81 THR LEU 82 HIS SER 78 HIS ILE 79 THR VAL 81 THR LEU 82 TYRSER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 PHE SER 78 HIS ILE 79 VAL VAL 81THR LEU 82 HIS SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 TYR SER 78 LYSILE 79 LEU VAL 81 THR LEU 82 PHE SER 78 LYS ILE 79 LEU VAL 81 THR LEU 82HIS SER 78 LYS ILE 79 LEU VAL 81 THR LEU 82 TYR SER 78 LYS ILE 79 METVAL 81 THR LEU 82 PHE SER 78 LYS ILE 79 MET VAL 81 THR LEU 82 HIS SER 78LYS ILE 79 MET VAL 81 THR LEU 82 TYR SER 78 LYS ILE 79 THR VAL 81 THRLEU 82 PHE SER 78 LYS ILE 79 THR VAL 81 THR LEU 82 HIS SER 78 LYS ILE 79THR VAL 81 THR LEU 82 TYR SER 78 LYS ILE 79 VAL VAL 81 THR LEU 82 PHESER 78 LYS ILE 79 VAL VAL 81 THR LEU 82 HIS SER 78 LYS ILE 79 VAL VAL 81THR LEU 82 TYR SER 78 TYR ILE 79 LEU VAL 81 THR LEU 82 PHE SER 78 TYRILE 79 LEU VAL 81 THR LEU 82 HIS SER 78 TYR ILE 79 LEU VAL 81 THR LEU 82TYR SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 PHE SER 78 TYR ILE 79 METVAL 81 THR LEU 82 HIS SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 TYR SER 78TYR ILE 79 THR VAL 81 THR LEU 82 PHE SER 78 TYR ILE 79 THR VAL 81 THRLEU 82 HIS SER 78 TYR ILE 79 THR VAL 81 THR LEU 82 TYR SER 78 TYR ILE 79VAL VAL 81 THR LEU 82 PHE SER 78 TYR ILE 79 VAL VAL 81 THR LEU 82 HISSER 78 TYR ILE 79 VAL VAL 81 THR LEU 82 TYR ASN 76 HIS ILE 79 LEU VAL 81THR LEU 82 PHE ASN 76 HIS ILE 79 LEU VAL 81 THR LEU 82 HIS ASN 76 HISILE 79 LEU VAL 81 THR LEU 82 TYR ASN 76 HIS ILE 79 MET VAL 81 THR LEU 82PHE ASN 76 HIS ILE 79 MET VAL 81 THR LEU 82 HIS ASN 76 HIS ILE 79 METVAL 81 THR LEU 82 TYR ASN 76 HIS ILE 79 THR VAL 81 THR LEU 82 PHE ASN 76HIS ILE 79 THR VAL 81 THR LEU 82 HIS ASN 76 HIS ILE 79 THR VAL 81 THRLEU 82 TYR ASN 76 HIS ILE 79 VAL VAL 81 THR LEU 82 PHE ASN 76 HIS ILE 79VAL VAL 81 THR LEU 82 HIS ASN 76 HIS ILE 79 VAL VAL 81 THR LEU 82 TYRASN 76 HIS SER 78 ASN VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ASN VAL 81THR LEU 82 HIS ASN 76 HIS SER 78 ASN VAL 81 THR LEU 82 TYR ASN 76 HISSER 78 THR VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 THR VAL 81 THR LEU 82HIS ASN 76 HIS SER 78 THR VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 ARGVAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ARG VAL 81 THR LEU 82 HIS ASN 76HIS SER 78 ARG VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 ASP VAL 81 THRLEU 82 PHE ASN 76 HIS SER 78 ASP VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78ASP VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 GLN VAL 81 THR LEU 82 PHEASN 76 HIS SER 78 GLN VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 GLN VAL 81THR LEU 82 TYR ASN 76 HIS SER 78 HIS VAL 81 THR LEU 82 PHE ASN 76 HISSER 78 HIS VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 HIS VAL 81 THR LEU 82TYR ASN 76 HIS SER 78 LYS VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 LYSVAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 LYS VAL 81 THR LEU 82 TYR ASN 76HIS SER 78 TYR VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 TYR VAL 81 THRLEU 82 HIS ASN 76 HIS SER 78 TYR VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78ASN ILE 79 LEU LEU 82 PHE ASN 76 HIS SER 78 ASN ILE 79 LEU LEU 82 HISASN 76 HIS SER 78 ASN ILE 79 LEU LEU 82 TYR ASN 76 HIS SER 78 ASN ILE 79MET LEU 82 PHE ASN 76 HIS SER 78 ASN ILE 79 MET LEU 82 HIS ASN 76 HISSER 78 ASN ILE 79 MET LEU 82 TYR ASN 76 HIS SER 78 ASN ILE 79 THR LEU 82PHE ASN 76 HIS SER 78 ASN ILE 79 THR LEU 82 HIS ASN 76 HIS SER 78 ASNILE 79 THR LEU 82 TYR ASN 76 HIS SER 78 ASN ILE 79 VAL LEU 82 PHE ASN 76HIS SER 78 ASN ILE 79 VAL LEU 82 HIS ASN 76 HIS SER 78 ASN ILE 79 VALLEU 82 TYR ASN 76 HIS SER 78 THR ILE 79 LEU LEU 82 PHE ASN 76 HIS SER 78THR ILE 79 LEU LEU 82 HIS ASN 76 HIS SER 78 THR ILE 79 LEU LEU 82 TYRASN 76 HIS SER 78 THR ILE 79 MET LEU 82 PHE ASN 76 HIS SER 78 THR ILE 79MET LEU 82 HIS ASN 76 HIS SER 78 THR ILE 79 MET LEU 82 TYR ASN 76 HISSER 78 THR ILE 79 THR LEU 82 PHE ASN 76 HIS SER 78 THR ILE 79 THR LEU 82HIS ASN 76 HIS SER 78 THR ILE 79 THR LEU 82 TYR ASN 76 HIS SER 78 THRILE 79 VAL LEU 82 PHE ASN 76 HIS SER 78 THR ILE 79 VAL LEU 82 HIS ASN 76HIS SER 78 THR ILE 79 VAL LEU 82 TYR ASN 76 HIS SER 78 ARG ILE 79 LEULEU 82 PHE ASN 76 HIS SER 78 ARG ILE 79 LEU LEU 82 HIS ASN 76 HIS SER 78ARG ILE 79 LEU LEU 82 TYR ASN 76 HIS SER 78 ARG ILE 79 MET LEU 82 PHEASN 76 HIS SER 78 ARG ILE 79 MET LEU 82 HIS ASN 76 HIS SER 78 ARG ILE 79MET LEU 82 TYR ASN 76 HIS SER 78 ARG ILE 79 THR LEU 82 PHE ASN 76 HISSER 78 ARG ILE 79 THR LEU 82 HIS ASN 76 HIS SER 78 ARG ILE 79 THR LEU 82TYR ASN 76 HIS SER 78 ARG ILE 79 VAL LEU 82 PHE ASN 76 HIS SER 78 ARGILE 79 VAL LEU 82 HIS ASN 76 HIS SER 78 ARG ILE 79 VAL LEU 82 TYR ASN 76HIS SER 78 ASP ILE 79 LEU LEU 82 PHE ASN 76 HIS SER 78 ASP ILE 79 LEULEU 82 HIS ASN 76 HIS SER 78 ASP ILE 79 LEU LEU 82 TYR ASN 76 HIS SER 78ASP ILE 79 MET LEU 82 PHE ASN 76 HIS SER 78 ASP ILE 79 MET LEU 82 HISASN 76 HIS SER 78 ASP ILE 79 MET LEU 82 TYR ASN 76 HIS SER 78 ASP ILE 79THR LEU 82 PHE ASN 76 HIS SER 78 ASP ILE 79 THR LEU 82 HIS ASN 76 HISSER 78 ASP ILE 79 THR LEU 82 TYR ASN 76 HIS SER 78 ASP ILE 79 VAL LEU 82PHE ASN 76 HIS SER 78 ASP ILE 79 VAL LEU 82 HIS ASN 76 HIS SER 78 ASPILE 79 VAL LEU 82 TYR ASN 76 HIS SER 78 GLN ILE 79 LEU LEU 82 PHE ASN 76HIS SER 78 GLN ILE 79 LEU LEU 82 HIS ASN 76 HIS SER 78 GLN ILE 79 LEULEU 82 TYR ASN 76 HIS SER 78 GLN ILE 79 MET LEU 82 PHE ASN 76 HIS SER 78GLN ILE 79 MET LEU 82 HIS ASN 76 HIS SER 78 GLN ILE 79 MET LEU 82 TYRASN 76 HIS SER 78 GLN ILE 79 THR LEU 82 PHE ASN 76 HIS SER 78 GLN ILE 79THR LEU 82 HIS ASN 76 HIS SER 78 GLN ILE 79 THR LEU 82 TYR ASN 76 HISSER 78 GLN ILE 79 VAL LEU 82 PHE ASN 76 HIS SER 78 GLN ILE 79 VAL LEU 82HIS ASN 76 HIS SER 78 GLN ILE 79 VAL LEU 82 TYR ASN 76 HIS SER 78 HISILE 79 LEU LEU 82 PHE ASN 76 HIS SER 78 HIS ILE 79 LEU LEU 82 HIS ASN 76HIS SER 78 HIS ILE 79 LEU LEU 82 TYR ASN 76 HIS SER 78 HIS ILE 79 METLEU 82 PHE ASN 76 HIS SER 78 HIS ILE 79 MET LEU 82 HIS ASN 76 HIS SER 78HIS ILE 79 MET LEU 82 TYR ASN 76 HIS SER 78 HIS ILE 79 THR LEU 82 PHEASN 76 HIS SER 78 HIS ILE 79 THR LEU 82 HIS ASN 76 HIS SER 78 HIS ILE 79THR LEU 82 TYR ASN 76 HIS SER 78 HIS ILE 79 VAL LEU 82 PHE ASN 76 HISSER 78 HIS ILE 79 VAL LEU 82 HIS ASN 76 HIS SER 78 HIS ILE 79 VAL LEU 82TYR ASN 76 HIS SER 78 LYS ILE 79 LEU LEU 82 PHE ASN 76 HIS SER 78 LYSILE 79 LEU LEU 82 HIS ASN 76 HIS SER 78 LYS ILE 79 LEU LEU 82 TYR ASN 76HIS SER 78 LYS ILE 79 MET LEU 82 PHE ASN 76 HIS SER 78 LYS ILE 79 METLEU 82 HIS ASN 76 HIS SER 78 LYS ILE 79 MET LEU 82 TYR ASN 76 HIS SER 78LYS ILE 79 THR LEU 82 PHE ASN 76 HIS SER 78 LYS ILE 79 THR LEU 82 HISASN 76 HIS SER 78 LYS ILE 79 THR LEU 82 TYR ASN 76 HIS SER 78 LYS ILE 79VAL LEU 82 PHE ASN 76 HIS SER 78 LYS ILE 79 VAL LEU 82 HIS ASN 76 HISSER 78 LYS ILE 79 VAL LEU 82 TYR ASN 76 HIS SER 78 TYR ILE 79 LEU LEU 82PHE ASN 76 HIS SER 78 TYR ILE 79 LEU LEU 82 HIS ASN 76 HIS SER 78 TYRILE 79 LEU LEU 82 TYR ASN 76 HIS SER 78 TYR ILE 79 MET LEU 82 PHE ASN 76HIS SER 78 TYR ILE 79 MET LEU 82 HIS ASN 76 HIS SER 78 TYR ILE 79 METLEU 82 TYR ASN 76 HIS SER 78 TYR ILE 79 THR LEU 82 PHE ASN 76 HIS SER 78TYR ILE 79 THR LEU 82 HIS ASN 76 HIS SER 78 TYR ILE 79 THR LEU 82 TYRASN 76 HIS SER 78 TYR ILE 79 VAL LEU 82 PHE ASN 76 HIS SER 78 TYR ILE 79VAL LEU 82 HIS ASN 76 HIS SER 78 TYR ILE 79 VAL LEU 82 TYR ASN 76 HISSER 78 ASN ILE 79 LEU VAL 81 THR ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81THR ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81 THR ASN 76 HIS SER 78 ASNILE 79 VAL VAL 81 THR ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR ASN 76HIS SER 78 THR ILE 79 MET VAL 81 THR ASN 76 HIS SER 78 THR ILE 79 THRVAL 81 THR ASN 76 HIS SER 78 THR ILE 79 VAL VAL 81 THR ASN 76 HIS SER 78ARG ILE 79 LEU VAL 81 THR ASN 76 HIS SER 78 ARG ILE 79 MET VAL 81 THRASN 76 HIS SER 78 ARG ILE 79 THR VAL 81 THR ASN 76 HIS SER 78 ARG ILE 79VAL VAL 81 THR ASN 76 HIS SER 78 ASP ILE 79 LEU VAL 81 THR ASN 76 HISSER 78 ASP ILE 79 MET VAL 81 THR ASN 76 HIS SER 78 ASP ILE 79 THR VAL 81THR ASN 76 HIS SER 78 ASP ILE 79 VAL VAL 81 THR ASN 76 HIS SER 78 GLNILE 79 LEU VAL 81 THR ASN 76 HIS SER 78 GLN ILE 79 MET VAL 81 THR ASN 76HIS SER 78 GLN ILE 79 THR VAL 81 THR ASN 76 HIS SER 78 GLN ILE 79 VALVAL 81 THR ASN 76 HIS SER 78 HIS ILE 79 LEU VAL 81 THR ASN 76 HIS SER 78HIS ILE 79 MET VAL 81 THR ASN 76 HIS SER 78 HIS ILE 79 THR VAL 81 THRASN 76 HIS SER 78 HIS ILE 79 VAL VAL 81 THR ASN 76 HIS SER 78 LYS ILE 79LEU VAL 81 THR ASN 76 HIS SER 78 LYS ILE 79 MET VAL 81 THR ASN 76 HISSER 78 LYS ILE 79 THR VAL 81 THR ASN 76 HIS SER 78 LYS ILE 79 VAL VAL 81THR ASN 76 HIS SER 78 TYR ILE 79 LEU VAL 81 THR ASN 76 HIS SER 78 TYRILE 79 MET VAL 81 THR ASN 76 HIS SER 78 TYR ILE 79 THR VAL 81 THR ASN 76HIS SER 78 TYR ILE 79 VAL VAL 81 THR LEU 75 ILE ILE 79 LEU VAL 81 THRLEU 82 PHE LEU 75 ILE ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILE ILE 79LEU VAL 81 THR LEU 82 TYR LEU 75 ILE ILE 79 MET VAL 81 THR LEU 82 PHELEU 75 ILE ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILE ILE 79 MET VAL 81THR LEU 82 TYR LEU 75 ILE ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 ILEILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 ILE ILE 79 THR VAL 81 THR LEU 82TYR LEU 75 ILE ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 ILE ILE 79 VALVAL 81 THR LEU 82 HIS LEU 75 ILE ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75MET ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET ILE 79 LEU VAL 81 THRLEU 82 HIS LEU 75 MET ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 MET ILE 79MET VAL 81 THR LEU 82 PHE LEU 75 MET ILE 79 MET VAL 81 THR LEU 82 HISLEU 75 MET ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 MET ILE 79 THR VAL 81THR LEU 82 PHE LEU 75 MET ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 METILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 MET ILE 79 VAL VAL 81 THR LEU 82PHE LEU 75 MET ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 MET ILE 79 VALVAL 81 THR LEU 82 TYR LEU 75 VAL ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75VAL ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 VAL ILE 79 LEU VAL 81 THRLEU 82 TYR LEU 75 VAL ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL ILE 79MET VAL 81 THR LEU 82 HIS LEU 75 VAL ILE 79 MET VAL 81 THR LEU 82 TYRLEU 75 VAL ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 VAL ILE 79 THR VAL 81THR LEU 82 HIS LEU 75 VAL ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 VALILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 VAL ILE 79 VAL VAL 81 THR LEU 82HIS LEU 75 VAL ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 ASNVAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 ASN VAL 81 THR LEU 82 HIS LEU 75ILE SER 78 ASN VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 THR VAL 81 THRLEU 82 PHE LEU 75 ILE SER 78 THR VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78THR VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 ARG VAL 81 THR LEU 82 PHELEU 75 ILE SER 78 ARG VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 ARG VAL 81THR LEU 82 TYR LEU 75 ILE SER 78 ASP VAL 81 THR LEU 82 PHE LEU 75 ILESER 78 ASP VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 ASP VAL 81 THR LEU 82TYR LEU 75 ILE SER 78 GLN VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 GLNVAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 GLN VAL 81 THR LEU 82 TYR LEU 75ILE SER 78 HIS VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 HIS VAL 81 THRLEU 82 HIS LEU 75 ILE SER 78 HIS VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78LYS VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 LYS VAL 81 THR LEU 82 HISLEU 75 ILE SER 78 LYS VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 TYR VAL 81THR LEU 82 PHE LEU 75 ILE SER 78 TYR VAL 81 THR LEU 82 HIS LEU 75 ILESER 78 TYR VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 ASN VAL 81 THR LEU 82PHE LEU 75 MET SER 78 ASN VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 ASNVAL 81 THR LEU 82 TYR LEU 75 MET SER 78 THR VAL 81 THR LEU 82 PHE LEU 75MET SER 78 THR VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 THR VAL 81 THRLEU 82 TYR LEU 75 MET SER 78 ARG VAL 81 THR LEU 82 PHE LEU 75 MET SER 78ARG VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 ARG VAL 81 THR LEU 82 TYRLEU 75 MET SER 78 ASP VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 ASP VAL 81THR LEU 82 HIS LEU 75 MET SER 78 ASP VAL 81 THR LEU 82 TYR LEU 75 METSER 78 GLN VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 GLN VAL 81 THR LEU 82HIS LEU 75 MET SER 78 GLN VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 HISVAL 81 THR LEU 82 PHE LEU 75 MET SER 78 HIS VAL 81 THR LEU 82 HIS LEU 75MET SER 78 HIS VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 LYS VAL 81 THRLEU 82 PHE LEU 75 MET SER 78 LYS VAL 81 THR LEU 82 HIS LEU 75 MET SER 78LYS VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 TYR VAL 81 THR LEU 82 PHELEU 75 MET SER 78 TYR VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 TYR VAL 81THR LEU 82 TYR LEU 75 VAL SER 78 ASN VAL 81 THR LEU 82 PHE LEU 75 VALSER 78 ASN VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 ASN VAL 81 THR LEU 82TYR LEU 75 VAL SER 78 THR VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 THRVAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 THR VAL 81 THR LEU 82 TYR LEU 75VAL SER 78 ARG VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 ARG VAL 81 THRLEU 82 HIS LEU 75 VAL SER 78 ARG VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78ASP VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 ASP VAL 81 THR LEU 82 HISLEU 75 VAL SER 78 ASP VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 GLN VAL 81THR LEU 82 PHE LEU 75 VAL SER 78 GLN VAL 81 THR LEU 82 HIS LEU 75 VALSER 78 GLN VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 HIS VAL 81 THR LEU 82PHE LEU 75 VAL SER 78 HIS VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 HISVAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 LYS VAL 81 THR LEU 82 PHE LEU 75VAL SER 78 LYS VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 LYS VAL 81 THRLEU 82 TYR LEU 75 VAL SER 78 TYR VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78TYR VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 TYR VAL 81 THR LEU 82 TYRLEU 75 ILE SER 78 ASN ILE 79 LEU LEU 82 PHE LEU 75 ILE SER 78 ASN ILE 79LEU LEU 82 HIS LEU 75 ILE SER 78 ASN ILE 79 LEU LEU 82 TYR LEU 75 ILESER 78 ASN ILE 79 MET LEU 82 PHE LEU 75 ILE SER 78 ASN ILE 79 MET LEU 82HIS LEU 75 ILE SER 78 ASN ILE 79 MET LEU 82 TYR LEU 75 ILE SER 78 ASNILE 79 THR LEU 82 PHE LEU 75 ILE SER 78 ASN ILE 79 THR LEU 82 HIS LEU 75ILE SER 78 ASN ILE 79 THR LEU 82 TYR LEU 75 ILE SER 78 ASN ILE 79 VALLEU 82 PHE LEU 75 ILE SER 78 ASN ILE 79 VAL LEU 82 HIS LEU 75 ILE SER 78ASN ILE 79 VAL LEU 82 TYR LEU 75 ILE SER 78 THR ILE 79 LEU LEU 82 PHELEU 75 ILE SER 78 THR ILE 79 LEU LEU 82 HIS LEU 75 ILE SER 78 THR ILE 79LEU LEU 82 TYR LEU 75 ILE SER 78 THR ILE 79 MET LEU 82 PHE LEU 75 ILESER 78 THR ILE 79 MET LEU 82 HIS LEU 75 ILE SER 78 THR ILE 79 MET LEU 82TYR LEU 75 ILE SER 78 THR ILE 79 THR LEU 82 PHE LEU 75 ILE SER 78 THRILE 79 THR LEU 82 HIS LEU 75 ILE SER 78 THR ILE 79 THR LEU 82 TYR LEU 75ILE SER 78 THR ILE 79 VAL LEU 82 PHE LEU 75 ILE SER 78 THR ILE 79 VALLEU 82 HIS LEU 75 ILE SER 78 THR ILE 79 VAL LEU 82 TYR LEU 75 ILE SER 78ARG ILE 79 LEU LEU 82 PHE LEU 75 ILE SER 78 ARG ILE 79 LEU LEU 82 HISLEU 75 ILE SER 78 ARG ILE 79 LEU LEU 82 TYR LEU 75 ILE SER 78 ARG ILE 79MET LEU 82 PHE LEU 75 ILE SER 78 ARG ILE 79 MET LEU 82 HIS LEU 75 ILESER 78 ARG ILE 79 MET LEU 82 TYR LEU 75 ILE SER 78 ARG ILE 79 THR LEU 82PHE LEU 75 ILE SER 78 ARG ILE 79 THR LEU 82 HIS LEU 75 ILE SER 78 ARGILE 79 THR LEU 82 TYR LEU 75 ILE SER 78 ARG ILE 79 VAL LEU 82 PHE LEU 75ILE SER 78 ARG ILE 79 VAL LEU 82 HIS LEU 75 ILE SER 78 ARG ILE 79 VALLEU 82 TYR LEU 75 ILE SER 78 ASP ILE 79 LEU LEU 82 PHE LEU 75 ILE SER 78ASP ILE 79 LEU LEU 82 HIS LEU 75 ILE SER 78 ASP ILE 79 LEU LEU 82 TYRLEU 75 ILE SER 78 ASP ILE 79 MET LEU 82 PHE LEU 75 ILE SER 78 ASP ILE 79MET LEU 82 HIS LEU 75 ILE SER 78 ASP ILE 79 MET LEU 82 TYR LEU 75 ILESER 78 ASP ILE 79 THR LEU 82 PHE LEU 75 ILE SER 78 ASP ILE 79 THR LEU 82HIS LEU 75 ILE SER 78 ASP ILE 79 THR LEU 82 TYR LEU 75 ILE SER 78 ASPILE 79 VAL LEU 82 PHE LEU 75 ILE SER 78 ASP ILE 79 VAL LEU 82 HIS LEU 75ILE SER 78 ASP ILE 79 VAL LEU 82 TYR LEU 75 ILE SER 78 GLN ILE 79 LEULEU 82 PHE LEU 75 ILE SER 78 GLN ILE 79 LEU LEU 82 HIS LEU 75 ILE SER 78GLN ILE 79 LEU LEU 82 TYR LEU 75 ILE SER 78 GLN ILE 79 MET LEU 82 PHELEU 75 ILE SER 78 GLN ILE 79 MET LEU 82 HIS LEU 75 ILE SER 78 GLN ILE 79MET LEU 82 TYR LEU 75 ILE SER 78 GLN ILE 79 THR LEU 82 PHE LEU 75 ILESER 78 GLN ILE 79 THR LEU 82 HIS LEU 75 ILE SER 78 GLN ILE 79 THR LEU 82TYR LEU 75 ILE SER 78 GLN ILE 79 VAL LEU 82 PHE LEU 75 ILE SER 78 GLNILE 79 VAL LEU 82 HIS LEU 75 ILE SER 78 GLN ILE 79 VAL LEU 82 TYR LEU 75ILE SER 78 HIS ILE 79 LEU LEU 82 PHE LEU 75 ILE SER 78 HIS ILE 79 LEULEU 82 HIS LEU 75 ILE SER 78 HIS ILE 79 LEU LEU 82 TYR LEU 75 ILE SER 78HIS ILE 79 MET LEU 82 PHE LEU 75 ILE SER 78 HIS ILE 79 MET LEU 82 HISLEU 75 ILE SER 78 HIS ILE 79 MET LEU 82 TYR LEU 75 ILE SER 78 HIS ILE 79THR LEU 82 PHE LEU 75 ILE SER 78 HIS ILE 79 THR LEU 82 HIS LEU 75 ILESER 78 HIS ILE 79 THR LEU 82 TYR LEU 75 ILE SER 78 HIS ILE 79 VAL LEU 82PHE LEU 75 ILE SER 78 HIS ILE 79 VAL LEU 82 HIS LEU 75 ILE SER 78 HISILE 79 VAL LEU 82 TYR LEU 75 ILE SER 78 LYS ILE 79 LEU LEU 82 PHE LEU 75ILE SER 78 LYS ILE 79 LEU LEU 82 HIS LEU 75 ILE SER 78 LYS ILE 79 LEULEU 82 TYR LEU 75 ILE SER 78 LYS ILE 79 MET LEU 82 PHE LEU 75 ILE SER 78LYS ILE 79 MET LEU 82 HIS LEU 75 ILE SER 78 LYS ILE 79 MET LEU 82 TYRLEU 75 ILE SER 78 LYS ILE 79 THR LEU 82 PHE LEU 75 ILE SER 78 LYS ILE 79THR LEU 82 HIS LEU 75 ILE SER 78 LYS ILE 79 THR LEU 82 TYR LEU 75 ILESER 78 LYS ILE 79 VAL LEU 82 PHE LEU 75 ILE SER 78 LYS ILE 79 VAL LEU 82HIS LEU 75 ILE SER 78 LYS ILE 79 VAL LEU 82 TYR LEU 75 ILE SER 78 TYRILE 79 LEU LEU 82 PHE LEU 75 ILE SER 78 TYR ILE 79 LEU LEU 82 HIS LEU 75ILE SER 78 TYR ILE 79 LEU LEU 82 TYR LEU 75 ILE SER 78 TYR ILE 79 METLEU 82 PHE LEU 75 ILE SER 78 TYR ILE 79 MET LEU 82 HIS LEU 75 ILE SER 78TYR ILE 79 MET LEU 82 TYR LEU 75 ILE SER 78 TYR ILE 79 THR LEU 82 PHELEU 75 ILE SER 78 TYR ILE 79 THR LEU 82 HIS LEU 75 ILE SER 78 TYR ILE 79THR LEU 82 TYR LEU 75 ILE SER 78 TYR ILE 79 VAL LEU 82 PHE LEU 75 ILESER 78 TYR ILE 79 VAL LEU 82 HIS LEU 75 ILE SER 78 TYR ILE 79 VAL LEU 82TYR LEU 75 MET SER 78 ASN ILE 79 LEU LEU 82 PHE LEU 75 MET SER 78 ASNILE 79 LEU LEU 82 HIS LEU 75 MET SER 78 ASN ILE 79 LEU LEU 82 TYR LEU 75MET SER 78 ASN ILE 79 MET LEU 82 PHE LEU 75 MET SER 78 ASN ILE 79 METLEU 82 HIS LEU 75 MET SER 78 ASN ILE 79 MET LEU 82 TYR LEU 75 MET SER 78ASN ILE 79 THR LEU 82 PHE LEU 75 MET SER 78 ASN ILE 79 THR LEU 82 HISLEU 75 MET SER 78 ASN ILE 79 THR LEU 82 TYR LEU 75 MET SER 78 ASN ILE 79VAL LEU 82 PHE LEU 75 MET SER 78 ASN ILE 79 VAL LEU 82 HIS LEU 75 METSER 78 ASN ILE 79 VAL LEU 82 TYR LEU 75 MET SER 78 THR ILE 79 LEU LEU 82PHE LEU 75 MET SER 78 THR ILE 79 LEU LEU 82 HIS LEU 75 MET SER 78 THRILE 79 LEU LEU 82 TYR LEU 75 MET SER 78 THR ILE 79 MET LEU 82 PHE LEU 75MET SER 78 THR ILE 79 MET LEU 82 HIS LEU 75 MET SER 78 THR ILE 79 METLEU 82 TYR LEU 75 MET SER 78 THR ILE 79 THR LEU 82 PHE LEU 75 MET SER 78THR ILE 79 THR LEU 82 HIS LEU 75 MET SER 78 THR ILE 79 THR LEU 82 TYRLEU 75 MET SER 78 THR ILE 79 VAL LEU 82 PHE LEU 75 MET SER 78 THR ILE 79VAL LEU 82 HIS LEU 75 MET SER 78 THR ILE 79 VAL LEU 82 TYR LEU 75 METSER 78 ARG ILE 79 LEU LEU 82 PHE LEU 75 MET SER 78 ARG ILE 79 LEU LEU 82HIS LEU 75 MET SER 78 ARG ILE 79 LEU LEU 82 TYR LEU 75 MET SER 78 ARGILE 79 MET LEU 82 PHE LEU 75 MET SER 78 ARG ILE 79 MET LEU 82 HIS LEU 75MET SER 78 ARG ILE 79 MET LEU 82 TYR LEU 75 MET SER 78 ARG ILE 79 THRLEU 82 PHE LEU 75 MET SER 78 ARG ILE 79 THR LEU 82 HIS LEU 75 MET SER 78ARG ILE 79 THR LEU 82 TYR LEU 75 MET SER 78 ARG ILE 79 VAL LEU 82 PHELEU 75 MET SER 78 ARG ILE 79 VAL LEU 82 HIS LEU 75 MET SER 78 ARG ILE 79VAL LEU 82 TYR LEU 75 MET SER 78 ASP ILE 79 LEU LEU 82 PHE LEU 75 METSER 78 ASP ILE 79 LEU LEU 82 HIS LEU 75 MET SER 78 ASP ILE 79 LEU LEU 82TYR LEU 75 MET SER 78 ASP ILE 79 MET LEU 82 PHE LEU 75 MET SER 78 ASPILE 79 MET LEU 82 HIS LEU 75 MET SER 78 ASP ILE 79 MET LEU 82 TYR LEU 75MET SER 78 ASP ILE 79 THR LEU 82 PHE LEU 75 MET SER 78 ASP ILE 79 THRLEU 82 HIS LEU 75 MET SER 78 ASP ILE 79 THR LEU 82 TYR LEU 75 MET SER 78ASP ILE 79 VAL LEU 82 PHE LEU 75 MET SER 78 ASP ILE 79 VAL LEU 82 HISLEU 75 MET SER 78 ASP ILE 79 VAL LEU 82 TYR LEU 75 MET SER 78 GLN ILE 79LEU LEU 82 PHE LEU 75 MET SER 78 GLN ILE 79 LEU LEU 82 HIS LEU 75 METSER 78 GLN ILE 79 LEU LEU 82 TYR LEU 75 MET SER 78 GLN ILE 79 MET LEU 82PHE LEU 75 MET SER 78 GLN ILE 79 MET LEU 82 HIS LEU 75 MET SER 78 GLNILE 79 MET LEU 82 TYR LEU 75 MET SER 78 GLN ILE 79 THR LEU 82 PHE LEU 75MET SER 78 GLN ILE 79 THR LEU 82 HIS LEU 75 MET SER 78 GLN ILE 79 THRLEU 82 TYR LEU 75 MET SER 78 GLN ILE 79 VAL LEU 82 PHE LEU 75 MET SER 78GLN ILE 79 VAL LEU 82 HIS LEU 75 MET SER 78 GLN ILE 79 VAL LEU 82 TYRLEU 75 MET SER 78 HIS ILE 79 LEU LEU 82 PHE LEU 75 MET SER 78 HIS ILE 79LEU LEU 82 HIS LEU 75 MET SER 78 HIS ILE 79 LEU LEU 82 TYR LEU 75 METSER 78 HIS ILE 79 MET LEU 82 PHE LEU 75 MET SER 78 HIS ILE 79 MET LEU 82HIS LEU 75 MET SER 78 HIS ILE 79 MET LEU 82 TYR LEU 75 MET SER 78 HISILE 79 THR LEU 82 PHE LEU 75 MET SER 78 HIS ILE 79 THR LEU 82 HIS LEU 75MET SER 78 HIS ILE 79 THR LEU 82 TYR LEU 75 MET SER 78 HIS ILE 79 VALLEU 82 PHE LEU 75 MET SER 78 HIS ILE 79 VAL LEU 82 HIS LEU 75 MET SER 78HIS ILE 79 VAL LEU 82 TYR LEU 75 MET SER 78 LYS ILE 79 LEU LEU 82 PHELEU 75 MET SER 78 LYS ILE 79 LEU LEU 82 HIS LEU 75 MET SER 78 LYS ILE 79LEU LEU 82 TYR LEU 75 MET SER 78 LYS ILE 79 MET LEU 82 PHE LEU 75 METSER 78 LYS ILE 79 MET LEU 82 HIS LEU 75 MET SER 78 LYS ILE 79 MET LEU 82TYR LEU 75 MET SER 78 LYS ILE 79 THR LEU 82 PHE LEU 75 MET SER 78 LYSILE 79 THR LEU 82 HIS LEU 75 MET SER 78 LYS ILE 79 THR LEU 82 TYR LEU 75MET SER 78 LYS ILE 79 VAL LEU 82 PHE LEU 75 MET SER 78 LYS ILE 79 VALLEU 82 HIS LEU 75 MET SER 78 LYS ILE 79 VAL LEU 82 TYR LEU 75 MET SER 78TYR ILE 79 LEU LEU 82 PHE LEU 75 MET SER 78 TYR ILE 79 LEU LEU 82 HISLEU 75 MET SER 78 TYR ILE 79 LEU LEU 82 TYR LEU 75 MET SER 78 TYR ILE 79MET LEU 82 PHE LEU 75 MET SER 78 TYR ILE 79 MET LEU 82 HIS LEU 75 METSER 78 TYR ILE 79 MET LEU 82 TYR LEU 75 MET SER 78 TYR ILE 79 THR LEU 82PHE LEU 75 MET SER 78 TYR ILE 79 THR LEU 82 HIS LEU 75 MET SER 78 TYRILE 79 THR LEU 82 TYR LEU 75 MET SER 78 TYR ILE 79 VAL LEU 82 PHE LEU 75MET SER 78 TYR ILE 79 VAL LEU 82 HIS LEU 75 MET SER 78 TYR ILE 79 VALLEU 82 TYR LEU 75 VAL SER 78 ASN ILE 79 LEU LEU 82 PHE LEU 75 VAL SER 78ASN ILE 79 LEU LEU 82 HIS LEU 75 VAL SER 78 ASN ILE 79 LEU LEU 82 TYRLEU 75 VAL SER 78 ASN ILE 79 MET LEU 82 PHE LEU 75 VAL SER 78 ASN ILE 79MET LEU 82 HIS LEU 75 VAL SER 78 ASN ILE 79 MET LEU 82 TYR LEU 75 VALSER 78 ASN ILE 79 THR LEU 82 PHE LEU 75 VAL SER 78 ASN ILE 79 THR LEU 82HIS LEU 75 VAL SER 78 ASN ILE 79 THR LEU 82 TYR LEU 75 VAL SER 78 ASNILE 79 VAL LEU 82 PHE LEU 75 VAL SER 78 ASN ILE 79 VAL LEU 82 HIS LEU 75VAL SER 78 ASN ILE 79 VAL LEU 82 TYR LEU 75 VAL SER 78 THR ILE 79 LEULEU 82 PHE LEU 75 VAL SER 78 THR ILE 79 LEU LEU 82 HIS LEU 75 VAL SER 78THR ILE 79 LEU LEU 82 TYR LEU 75 VAL SER 78 THR ILE 79 MET LEU 82 PHELEU 75 VAL SER 78 THR ILE 79 MET LEU 82 HIS LEU 75 VAL SER 78 THR ILE 79MET LEU 82 TYR LEU 75 VAL SER 78 THR ILE 79 THR LEU 82 PHE LEU 75 VALSER 78 THR ILE 79 THR LEU 82 HIS LEU 75 VAL SER 78 THR ILE 79 THR LEU 82TYR LEU 75 VAL SER 78 THR ILE 79 VAL LEU 82 PHE LEU 75 VAL SER 78 THRILE 79 VAL LEU 82 HIS LEU 75 VAL SER 78 THR ILE 79 VAL LEU 82 TYR LEU 75VAL SER 78 ARG ILE 79 LEU LEU 82 PHE LEU 75 VAL SER 78 ARG ILE 79 LEULEU 82 HIS LEU 75 VAL SER 78 ARG ILE 79 LEU LEU 82 TYR LEU 75 VAL SER 78ARG ILE 79 MET LEU 82 PHE LEU 75 VAL SER 78 ARG ILE 79 MET LEU 82 HISLEU 75 VAL SER 78 ARG ILE 79 MET LEU 82 TYR LEU 75 VAL SER 78 ARG ILE 79THR LEU 82 PHE LEU 75 VAL SER 78 ARG ILE 79 THR LEU 82 HIS LEU 75 VALSER 78 ARG ILE 79 THR LEU 82 TYR LEU 75 VAL SER 78 ARG ILE 79 VAL LEU 82PHE LEU 75 VAL SER 78 ARG ILE 79 VAL LEU 82 HIS LEU 75 VAL SER 78 ARGILE 79 VAL LEU 82 TYR LEU 75 VAL SER 78 ASP ILE 79 LEU LEU 82 PHE LEU 75VAL SER 78 ASP ILE 79 LEU LEU 82 HIS LEU 75 VAL SER 78 ASP ILE 79 LEULEU 82 TYR LEU 75 VAL SER 78 ASP ILE 79 MET LEU 82 PHE LEU 75 VAL SER 78ASP ILE 79 MET LEU 82 HIS LEU 75 VAL SER 78 ASP ILE 79 MET LEU 82 TYRLEU 75 VAL SER 78 ASP ILE 79 THR LEU 82 PHE LEU 75 VAL SER 78 ASP ILE 79THR LEU 82 HIS LEU 75 VAL SER 78 ASP ILE 79 THR LEU 82 TYR LEU 75 VALSER 78 ASP ILE 79 VAL LEU 82 PHE LEU 75 VAL SER 78 ASP ILE 79 VAL LEU 82HIS LEU 75 VAL SER 78 ASP ILE 79 VAL LEU 82 TYR LEU 75 VAL SER 78 GLNILE 79 LEU LEU 82 PHE LEU 75 VAL SER 78 GLN ILE 79 LEU LEU 82 HIS LEU 75VAL SER 78 GLN ILE 79 LEU LEU 82 TYR LEU 75 VAL SER 78 GLN ILE 79 METLEU 82 PHE LEU 75 VAL SER 78 GLN ILE 79 MET LEU 82 HIS LEU 75 VAL SER 78GLN ILE 79 MET LEU 82 TYR LEU 75 VAL SER 78 GLN ILE 79 THR LEU 82 PHELEU 75 VAL SER 78 GLN ILE 79 THR LEU 82 HIS LEU 75 VAL SER 78 GLN ILE 79THR LEU 82 TYR LEU 75 VAL SER 78 GLN ILE 79 VAL LEU 82 PHE LEU 75 VALSER 78 GLN ILE 79 VAL LEU 82 HIS LEU 75 VAL SER 78 GLN ILE 79 VAL LEU 82TYR LEU 75 VAL SER 78 HIS ILE 79 LEU LEU 82 PHE LEU 75 VAL SER 78 HISILE 79 LEU LEU 82 HIS LEU 75 VAL SER 78 HIS ILE 79 LEU LEU 82 TYR LEU 75VAL SER 78 HIS ILE 79 MET LEU 82 PHE LEU 75 VAL SER 78 HIS ILE 79 METLEU 82 HIS LEU 75 VAL SER 78 HIS ILE 79 MET LEU 82 TYR LEU 75 VAL SER 78HIS ILE 79 THR LEU 82 PHE LEU 75 VAL SER 78 HIS ILE 79 THR LEU 82 HISLEU 75 VAL SER 78 HIS ILE 79 THR LEU 82 TYR LEU 75 VAL SER 78 HIS ILE 79VAL LEU 82 PHE LEU 75 VAL SER 78 HIS ILE 79 VAL LEU 82 HIS LEU 75 VALSER 78 HIS ILE 79 VAL LEU 82 TYR LEU 75 VAL SER 78 LYS ILE 79 LEU LEU 82PHE LEU 75 VAL SER 78 LYS ILE 79 LEU LEU 82 HIS LEU 75 VAL SER 78 LYSILE 79 LEU LEU 82 TYR LEU 75 VAL SER 78 LYS ILE 79 MET LEU 82 PHE LEU 75VAL SER 78 LYS ILE 79 MET LEU 82 HIS LEU 75 VAL SER 78 LYS ILE 79 METLEU 82 TYR LEU 75 VAL SER 78 LYS ILE 79 THR LEU 82 PHE LEU 75 VAL SER 78LYS ILE 79 THR LEU 82 HIS LEU 75 VAL SER 78 LYS ILE 79 THR LEU 82 TYRLEU 75 VAL SER 78 LYS ILE 79 VAL LEU 82 PHE LEU 75 VAL SER 78 LYS ILE 79VAL LEU 82 HIS LEU 75 VAL SER 78 LYS ILE 79 VAL LEU 82 TYR LEU 75 VALSER 78 TYR ILE 79 LEU LEU 82 PHE LEU 75 VAL SER 78 TYR ILE 79 LEU LEU 82HIS LEU 75 VAL SER 78 TYR ILE 79 LEU LEU 82 TYR LEU 75 VAL SER 78 TYRILE 79 MET LEU 82 PHE LEU 75 VAL SER 78 TYR ILE 79 MET LEU 82 HIS LEU 75VAL SER 78 TYR ILE 79 MET LEU 82 TYR LEU 75 VAL SER 78 TYR ILE 79 THRLEU 82 PHE LEU 75 VAL SER 78 TYR ILE 79 THR LEU 82 HIS LEU 75 VAL SER 78TYR ILE 79 THR LEU 82 TYR LEU 75 VAL SER 78 TYR ILE 79 VAL LEU 82 PHELEU 75 VAL SER 78 TYR ILE 79 VAL LEU 82 HIS LEU 75 VAL SER 78 TYR ILE 79VAL LEU 82 TYR LEU 75 ILE SER 78 ASN ILE 79 LEU VAL 81 THR LEU 75 ILESER 78 ASN ILE 79 MET VAL 81 THR LEU 75 ILE SER 78 ASN ILE 79 THR VAL 81THR LEU 75 ILE SER 78 ASN ILE 79 VAL VAL 81 THR LEU 75 ILE SER 78 THRILE 79 LEU VAL 81 THR LEU 75 ILE SER 78 THR ILE 79 MET VAL 81 THR LEU 75ILE SER 78 THR ILE 79 THR VAL 81 THR LEU 75 ILE SER 78 THR ILE 79 VALVAL 81 THR LEU 75 ILE SER 78 ARG ILE 79 LEU VAL 81 THR LEU 75 ILE SER 78ARG ILE 79 MET VAL 81 THR LEU 75 ILE SER 78 ARG ILE 79 THR VAL 81 THRLEU 75 ILE SER 78 ARG ILE 79 VAL VAL 81 THR LEU 75 ILE SER 78 ASP ILE 79LEU VAL 81 THR LEU 75 ILE SER 78 ASP ILE 79 MET VAL 81 THR LEU 75 ILESER 78 ASP ILE 79 THR VAL 81 THR LEU 75 ILE SER 78 ASP ILE 79 VAL VAL 81THR LEU 75 ILE SER 78 GLN ILE 79 LEU VAL 81 THR LEU 75 ILE SER 78 GLNILE 79 MET VAL 81 THR LEU 75 ILE SER 78 GLN ILE 79 THR VAL 81 THR LEU 75ILE SER 78 GLN ILE 79 VAL VAL 81 THR LEU 75 ILE SER 78 HIS ILE 79 LEUVAL 81 THR LEU 75 ILE SER 78 HIS ILE 79 MET VAL 81 THR LEU 75 ILE SER 78HIS ILE 79 THR VAL 81 THR LEU 75 ILE SER 78 HIS ILE 79 VAL VAL 81 THRLEU 75 ILE SER 78 LYS ILE 79 LEU VAL 81 THR LEU 75 ILE SER 78 LYS ILE 79MET VAL 81 THR LEU 75 ILE SER 78 LYS ILE 79 THR VAL 81 THR LEU 75 ILESER 78 LYS ILE 79 VAL VAL 81 THR LEU 75 ILE SER 78 TYR ILE 79 LEU VAL 81THR LEU 75 ILE SER 78 TYR ILE 79 MET VAL 81 THR LEU 75 ILE SER 78 TYRILE 79 THR VAL 81 THR LEU 75 ILE SER 78 TYR ILE 79 VAL VAL 81 THR LEU 75MET SER 78 ASN ILE 79 LEU VAL 81 THR LEU 75 MET SER 78 ASN ILE 79 METVAL 81 THR LEU 75 MET SER 78 ASN ILE 79 THR VAL 81 THR LEU 75 MET SER 78ASN ILE 79 VAL VAL 81 THR LEU 75 MET SER 78 THR ILE 79 LEU VAL 81 THRLEU 75 MET SER 78 THR ILE 79 MET VAL 81 THR LEU 75 MET SER 78 THR ILE 79THR VAL 81 THR LEU 75 MET SER 78 THR ILE 79 VAL VAL 81 THR LEU 75 METSER 78 ARG ILE 79 LEU VAL 81 THR LEU 75 MET SER 78 ARG ILE 79 MET VAL 81THR LEU 75 MET SER 78 ARG ILE 79 THR VAL 81 THR LEU 75 MET SER 78 ARGILE 79 VAL VAL 81 THR LEU 75 MET SER 78 ASP ILE 79 LEU VAL 81 THR LEU 75MET SER 78 ASP ILE 79 MET VAL 81 THR LEU 75 MET SER 78 ASP ILE 79 THRVAL 81 THR LEU 75 MET SER 78 ASP ILE 79 VAL VAL 81 THR LEU 75 MET SER 78GLN ILE 79 LEU VAL 81 THR LEU 75 MET SER 78 GLN ILE 79 MET VAL 81 THRLEU 75 MET SER 78 GLN ILE 79 THR VAL 81 THR LEU 75 MET SER 78 GLN ILE 79VAL VAL 81 THR LEU 75 MET SER 78 HIS ILE 79 LEU VAL 81 THR LEU 75 METSER 78 HIS ILE 79 MET VAL 81 THR LEU 75 MET SER 78 HIS ILE 79 THR VAL 81THR LEU 75 MET SER 78 HIS ILE 79 VAL VAL 81 THR LEU 75 MET SER 78 LYSILE 79 LEU VAL 81 THR LEU 75 MET SER 78 LYS ILE 79 MET VAL 81 THR LEU 75MET SER 78 LYS ILE 79 THR VAL 81 THR LEU 75 MET SER 78 LYS ILE 79 VALVAL 81 THR LEU 75 MET SER 78 TYR ILE 79 LEU VAL 81 THR LEU 75 MET SER 78TYR ILE 79 MET VAL 81 THR LEU 75 MET SER 78 TYR ILE 79 THR VAL 81 THRLEU 75 MET SER 78 TYR ILE 79 VAL VAL 81 THR LEU 75 VAL SER 78 ASN ILE 79LEU VAL 81 THR LEU 75 VAL SER 78 ASN ILE 79 MET VAL 81 THR LEU 75 VALSER 78 ASN ILE 79 THR VAL 81 THR LEU 75 VAL SER 78 ASN ILE 79 VAL VAL 81THR LEU 75 VAL SER 78 THR ILE 79 LEU VAL 81 THR LEU 75 VAL SER 78 THRILE 79 MET VAL 81 THR LEU 75 VAL SER 78 THR ILE 79 THR VAL 81 THR LEU 75VAL SER 78 THR ILE 79 VAL VAL 81 THR LEU 75 VAL SER 78 ARG ILE 79 LEUVAL 81 THR LEU 75 VAL SER 78 ARG ILE 79 MET VAL 81 THR LEU 75 VAL SER 78ARG ILE 79 THR VAL 81 THR LEU 75 VAL SER 78 ARG ILE 79 VAL VAL 81 THRLEU 75 VAL SER 78 ASP ILE 79 LEU VAL 81 THR LEU 75 VAL SER 78 ASP ILE 79MET VAL 81 THR LEU 75 VAL SER 78 ASP ILE 79 THR VAL 81 THR LEU 75 VALSER 78 ASP ILE 79 VAL VAL 81 THR LEU 75 VAL SER 78 GLN ILE 79 LEU VAL 81THR LEU 75 VAL SER 78 GLN ILE 79 MET VAL 81 THR LEU 75 VAL SER 78 GLNILE 79 THR VAL 81 THR LEU 75 VAL SER 78 GLN ILE 79 VAL VAL 81 THR LEU 75VAL SER 78 HIS ILE 79 LEU VAL 81 THR LEU 75 VAL SER 78 HIS ILE 79 METVAL 81 THR LEU 75 VAL SER 78 HIS ILE 79 THR VAL 81 THR LEU 75 VAL SER 78HIS ILE 79 VAL VAL 81 THR LEU 75 VAL SER 78 LYS ILE 79 LEU VAL 81 THRLEU 75 VAL SER 78 LYS ILE 79 MET VAL 81 THR LEU 75 VAL SER 78 LYS ILE 79THR VAL 81 THR LEU 75 VAL SER 78 LYS ILE 79 VAL VAL 81 THR LEU 75 VALSER 78 TYR ILE 79 LEU VAL 81 THR LEU 75 VAL SER 78 TYR ILE 79 MET VAL 81THR LEU 75 VAL SER 78 TYR ILE 79 THR VAL 81 THR LEU 75 VAL SER 78 TYRILE 79 VAL VAL 81 THR LEU 75 ILE ASN 76 HIS VAL 81 THR LEU 82 PHE LEU 75ILE ASN 76 HIS VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS VAL 81 THRLEU 82 TYR LEU 75 MET ASN 76 HIS VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76HIS VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS VAL 81 THR LEU 82 TYRLEU 75 VAL ASN 76 HIS VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS VAL 81THR LEU 82 HIS LEU 75 VAL ASN 76 HIS VAL 81 THR LEU 82 TYR LEU 75 ILEASN 76 HIS ILE 79 LEU LEU 82 PHE LEU 75 ILE ASN 76 HIS ILE 79 LEU LEU 82HIS LEU 75 ILE ASN 76 HIS ILE 79 LEU LEU 82 TYR LEU 75 ILE ASN 76 HISILE 79 MET LEU 82 PHE LEU 75 ILE ASN 76 HIS ILE 79 MET LEU 82 HIS LEU 75ILE ASN 76 HIS ILE 79 MET LEU 82 TYR LEU 75 ILE ASN 76 HIS ILE 79 THRLEU 82 PHE LEU 75 ILE ASN 76 HIS ILE 79 THR LEU 82 HIS LEU 75 ILE ASN 76HIS ILE 79 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS ILE 79 VAL LEU 82 PHELEU 75 ILE ASN 76 HIS ILE 79 VAL LEU 82 HIS LEU 75 ILE ASN 76 HIS ILE 79VAL LEU 82 TYR LEU 75 MET ASN 76 HIS ILE 79 LEU LEU 82 PHE LEU 75 METASN 76 HIS ILE 79 LEU LEU 82 HIS LEU 75 MET ASN 76 HIS ILE 79 LEU LEU 82TYR LEU 75 MET ASN 76 HIS ILE 79 MET LEU 82 PHE LEU 75 MET ASN 76 HISILE 79 MET LEU 82 HIS LEU 75 MET ASN 76 HIS ILE 79 MET LEU 82 TYR LEU 75MET ASN 76 HIS ILE 79 THR LEU 82 PHE LEU 75 MET ASN 76 HIS ILE 79 THRLEU 82 HIS LEU 75 MET ASN 76 HIS ILE 79 THR LEU 82 TYR LEU 75 MET ASN 76HIS ILE 79 VAL LEU 82 PHE LEU 75 MET ASN 76 HIS ILE 79 VAL LEU 82 HISLEU 75 MET ASN 76 HIS ILE 79 VAL LEU 82 TYR LEU 75 VAL ASN 76 HIS ILE 79LEU LEU 82 PHE LEU 75 VAL ASN 76 HIS ILE 79 LEU LEU 82 HIS LEU 75 VALASN 76 HIS ILE 79 LEU LEU 82 TYR LEU 75 VAL ASN 76 HIS ILE 79 MET LEU 82PHE LEU 75 VAL ASN 76 HIS ILE 79 MET LEU 82 HIS LEU 75 VAL ASN 76 HISILE 79 MET LEU 82 TYR LEU 75 VAL ASN 76 HIS ILE 79 THR LEU 82 PHE LEU 75VAL ASN 76 HIS ILE 79 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS ILE 79 THRLEU 82 TYR LEU 75 VAL ASN 76 HIS ILE 79 VAL LEU 82 PHE LEU 75 VAL ASN 76HIS ILE 79 VAL LEU 82 HIS LEU 75 VAL ASN 76 HIS ILE 79 VAL LEU 82 TYRLEU 75 ILE ASN 76 HIS ILE 79 LEU VAL 81 THR LEU 75 ILE ASN 76 HIS ILE 79MET VAL 81 THR LEU 75 ILE ASN 76 HIS ILE 79 THR VAL 81 THR LEU 75 ILEASN 76 HIS ILE 79 VAL VAL 81 THR LEU 75 MET ASN 76 HIS ILE 79 LEU VAL 81THR LEU 75 MET ASN 76 HIS ILE 79 MET VAL 81 THR LEU 75 MET ASN 76 HISILE 79 THR VAL 81 THR LEU 75 MET ASN 76 HIS ILE 79 VAL VAL 81 THR LEU 75VAL ASN 76 HIS ILE 79 LEU VAL 81 THR LEU 75 VAL ASN 76 HIS ILE 79 METVAL 81 THR LEU 75 VAL ASN 76 HIS ILE 79 THR VAL 81 THR LEU 75 VAL ASN 76HIS ILE 79 VAL VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 ASN LEU 82 PHELEU 75 ILE ASN 76 HIS SER 78 ASN LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78ASN LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 THR LEU 82 PHE LEU 75 ILEASN 76 HIS SER 78 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 THR LEU 82TYR LEU 75 ILE ASN 76 HIS SER 78 ARG LEU 82 PHE LEU 75 ILE ASN 76 HISSER 78 ARG LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ARG LEU 82 TYR LEU 75ILE ASN 76 HIS SER 78 ASP LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASPLEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASP LEU 82 TYR LEU 75 ILE ASN 76HIS SER 78 GLN LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 GLN LEU 82 HISLEU 75 ILE ASN 76 HIS SER 78 GLN LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78HIS LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 HIS LEU 82 HIS LEU 75 ILEASN 76 HIS SER 78 HIS LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 LYS LEU 82PHE LEU 75 ILE ASN 76 HIS SER 78 LYS LEU 82 HIS LEU 75 ILE ASN 76 HISSER 78 LYS LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 TYR LEU 82 PHE LEU 75ILE ASN 76 HIS SER 78 TYR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 TYRLEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASN LEU 82 PHE LEU 75 MET ASN 76HIS SER 78 ASN LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASN LEU 82 TYRLEU 75 MET ASN 76 HIS SER 78 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 THR LEU 82 TYR LEU 75 METASN 76 HIS SER 78 ARG LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ARG LEU 82HIS LEU 75 MET ASN 76 HIS SER 78 ARG LEU 82 TYR LEU 75 MET ASN 76 HISSER 78 ASP LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASP LEU 82 HIS LEU 75MET ASN 76 HIS SER 78 ASP LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 GLNLEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 GLN LEU 82 HIS LEU 75 MET ASN 76HIS SER 78 GLN LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 HIS LEU 82 PHELEU 75 MET ASN 76 HIS SER 78 HIS LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78HIS LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 LYS LEU 82 PHE LEU 75 METASN 76 HIS SER 78 LYS LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 LYS LEU 82TYR LEU 75 MET ASN 76 HIS SER 78 TYR LEU 82 PHE LEU 75 MET ASN 76 HISSER 78 TYR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 TYR LEU 82 TYR LEU 75VAL ASN 76 HIS SER 78 ASN LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASNLEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASN LEU 82 TYR LEU 75 VAL ASN 76HIS SER 78 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 THR LEU 82 HISLEU 75 VAL ASN 76 HIS SER 78 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78ARG LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ARG LEU 82 HIS LEU 75 VALASN 76 HIS SER 78 ARG LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASP LEU 82PHE LEU 75 VAL ASN 76 HIS SER 78 ASP LEU 82 HIS LEU 75 VAL ASN 76 HISSER 78 ASP LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 GLN LEU 82 PHE LEU 75VAL ASN 76 HIS SER 78 GLN LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 GLNLEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 HIS LEU 82 PHE LEU 75 VAL ASN 76HIS SER 78 HIS LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 HIS LEU 82 TYRLEU 75 VAL ASN 76 HIS SER 78 LYS LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78LYS LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 LYS LEU 82 TYR LEU 75 VALASN 76 HIS SER 78 TYR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 TYR LEU 82HIS LEU 75 VAL ASN 76 HIS SER 78 TYR LEU 82 TYR LEU 75 ILE ASN 76 HISSER 78 ASN VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 THR VAL 81 THR LEU 75ILE ASN 76 HIS SER 78 ARG VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 ASPVAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 GLN VAL 81 THR LEU 75 ILE ASN 76HIS SER 78 HIS VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 LYS VAL 81 THRLEU 75 ILE ASN 76 HIS SER 78 TYR VAL 81 THR LEU 75 MET ASN 76 HIS SER 78ASN VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 THR VAL 81 THR LEU 75 METASN 76 HIS SER 78 ARG VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 ASP VAL 81THR LEU 75 MET ASN 76 HIS SER 78 GLN VAL 81 THR LEU 75 MET ASN 76 HISSER 78 HIS VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 LYS VAL 81 THR LEU 75MET ASN 76 HIS SER 78 TYR VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 ASNVAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 THR VAL 81 THR LEU 75 VAL ASN 76HIS SER 78 ARG VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 ASP VAL 81 THRLEU 75 VAL ASN 76 HIS SER 78 GLN VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78HIS VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 LYS VAL 81 THR LEU 75 VALASN 76 HIS SER 78 TYR VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79LEU LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 MET LEU 75 ILE ASN 76 HISSER 78 ASN ILE 79 THR LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 VAL LEU 75ILE ASN 76 HIS SER 78 THR ILE 79 LEU LEU 75 ILE ASN 76 HIS SER 78 THRILE 79 MET LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 THR LEU 75 ILE ASN 76HIS SER 78 THR ILE 79 VAL LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 LEULEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 MET LEU 75 ILE ASN 76 HIS SER 78ARG ILE 79 THR LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 VAL LEU 75 ILEASN 76 HIS SER 78 ASP ILE 79 LEU LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79MET LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 THR LEU 75 ILE ASN 76 HISSER 78 ASP ILE 79 VAL LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 LEU LEU 75ILE ASN 76 HIS SER 78 GLN ILE 79 MET LEU 75 ILE ASN 76 HIS SER 78 GLNILE 79 THR LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 VAL LEU 75 ILE ASN 76HIS SER 78 HIS ILE 79 LEU LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 METLEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 THR LEU 75 ILE ASN 76 HIS SER 78HIS ILE 79 VAL LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 LEU LEU 75 ILEASN 76 HIS SER 78 LYS ILE 79 MET LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79THR LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 VAL LEU 75 ILE ASN 76 HISSER 78 TYR ILE 79 LEU LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 MET LEU 75ILE ASN 76 HIS SER 78 TYR ILE 79 THR LEU 75 ILE ASN 76 HIS SER 78 TYRILE 79 VAL LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 LEU LEU 75 MET ASN 76HIS SER 78 ASN ILE 79 MET LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 THRLEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 VAL LEU 75 MET ASN 76 HIS SER 78THR ILE 79 LEU LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 MET LEU 75 METASN 76 HIS SER 78 THR ILE 79 THR LEU 75 MET ASN 76 HIS SER 78 THR ILE 79VAL LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 LEU LEU 75 MET ASN 76 HISSER 78 ARG ILE 79 MET LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 THR LEU 75MET ASN 76 HIS SER 78 ARG ILE 79 VAL LEU 75 MET ASN 76 HIS SER 78 ASPILE 79 LEU LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 MET LEU 75 MET ASN 76HIS SER 78 ASP ILE 79 THR LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 VALLEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 LEU LEU 75 MET ASN 76 HIS SER 78GLN ILE 79 MET LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 THR LEU 75 METASN 76 HIS SER 78 GLN ILE 79 VAL LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79LEU LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 MET LEU 75 MET ASN 76 HISSER 78 HIS ILE 79 THR LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 VAL LEU 75MET ASN 76 HIS SER 78 LYS ILE 79 LEU LEU 75 MET ASN 76 HIS SER 78 LYSILE 79 MET LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 THR LEU 75 MET ASN 76HIS SER 78 LYS ILE 79 VAL LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 LEULEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 MET LEU 75 MET ASN 76 HIS SER 78TYR ILE 79 THR LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 VAL LEU 75 VALASN 76 HIS SER 78 ASN ILE 79 LEU LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79MET LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 THR LEU 75 VAL ASN 76 HISSER 78 ASN ILE 79 VAL LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 LEU LEU 75VAL ASN 76 HIS SER 78 THR ILE 79 MET LEU 75 VAL ASN 76 HIS SER 78 THRILE 79 THR LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 VAL LEU 75 VAL ASN 76HIS SER 78 ARG ILE 79 LEU LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 METLEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 THR LEU 75 VAL ASN 76 HIS SER 78ARG ILE 79 VAL LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 LEU LEU 75 VALASN 76 HIS SER 78 ASP ILE 79 MET LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79THR LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 VAL LEU 75 VAL ASN 76 HISSER 78 GLN ILE 79 LEU LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 MET LEU 75VAL ASN 76 HIS SER 78 GLN ILE 79 THR LEU 75 VAL ASN 76 HIS SER 78 GLNILE 79 VAL LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 LEU LEU 75 VAL ASN 76HIS SER 78 HIS ILE 79 MET LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 THRLEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 VAL LEU 75 VAL ASN 76 HIS SER 78LYS ILE 79 LEU LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 MET LEU 75 VALASN 76 HIS SER 78 LYS ILE 79 THR LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79VAL LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 LEU LEU 75 VAL ASN 76 HISSER 78 TYR ILE 79 MET LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 THR LEU 75VAL ASN 76 HIS SER 78 TYR ILE 79 VAL

TABLE 6 Quintuple Substitution Variants ASN 76 HIS SER 78 ASN ILE 79 LEUVAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82HIS ASN 76 HIS SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 TYR ASN 76 HISSER 78 ASN ILE 79 MET VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ASN ILE 79MET VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81 THRLEU 82 TYR ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 PHE ASN 76HIS SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 ASNILE 79 THR VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81THR LEU 82 PHE ASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 HISASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78THR ILE 79 LEU VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 THR ILE 79 LEUVAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82TYR ASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THR LEU 82 PHE ASN 76 HISSER 78 THR ILE 79 MET VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 THR ILE 79MET VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 THR ILE 79 THR VAL 81 THRLEU 82 PHE ASN 76 HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 82 HIS ASN 76HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 THRILE 79 VAL VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 THR ILE 79 VAL VAL 81THR LEU 82 HIS ASN 76 HIS SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 TYRASN 76 HIS SER 78 ARG ILE 79 LEU VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78ARG ILE 79 LEU VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 ARG ILE 79 LEUVAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 ARG ILE 79 MET VAL 81 THR LEU 82PHE ASN 76 HIS SER 78 ARG ILE 79 MET VAL 81 THR LEU 82 HIS ASN 76 HISSER 78 ARG ILE 79 MET VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 ARG ILE 79THR VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ARG ILE 79 THR VAL 81 THRLEU 82 HIS ASN 76 HIS SER 78 ARG ILE 79 THR VAL 81 THR LEU 82 TYR ASN 76HIS SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ARGILE 79 VAL VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 ARG ILE 79 VAL VAL 81THR LEU 82 TYR ASN 76 HIS SER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 PHEASN 76 HIS SER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78ASP ILE 79 LEU VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 ASP ILE 79 METVAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ASP ILE 79 MET VAL 81 THR LEU 82HIS ASN 76 HIS SER 78 ASP ILE 79 MET VAL 81 THR LEU 82 TYR ASN 76 HISSER 78 ASP ILE 79 THR VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ASP ILE 79THR VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 ASP ILE 79 THR VAL 81 THRLEU 82 TYR ASN 76 HIS SER 78 ASP ILE 79 VAL VAL 81 THR LEU 82 PHE ASN 76HIS SER 78 ASP ILE 79 VAL VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 ASPILE 79 VAL VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 GLN ILE 79 LEU VAL 81THR LEU 82 PHE ASN 76 HIS SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 HISASN 76 HIS SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78GLN ILE 79 MET VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 GLN ILE 79 METVAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 GLN ILE 79 MET VAL 81 THR LEU 82TYR ASN 76 HIS SER 78 GLN ILE 79 THR VAL 81 THR LEU 82 PHE ASN 76 HISSER 78 GLN ILE 79 THR VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 GLN ILE 79THR VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 GLN ILE 79 VAL VAL 81 THRLEU 82 PHE ASN 76 HIS SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 HIS ASN 76HIS SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 HISILE 79 LEU VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 HIS ILE 79 LEU VAL 81THR LEU 82 HIS ASN 76 HIS SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 TYRASN 76 HIS SER 78 HIS ILE 79 MET VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78HIS ILE 79 MET VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 HIS ILE 79 METVAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 HIS ILE 79 THR VAL 81 THR LEU 82PHE ASN 76 HIS SER 78 HIS ILE 79 THR VAL 81 THR LEU 82 HIS ASN 76 HISSER 78 HIS ILE 79 THR VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 HIS ILE 79VAL VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 HIS ILE 79 VAL VAL 81 THRLEU 82 HIS ASN 76 HIS SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 TYR ASN 76HIS SER 78 LYS ILE 79 LEU VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 LYSILE 79 LEU VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 LYS ILE 79 LEU VAL 81THR LEU 82 TYR ASN 76 HIS SER 78 LYS ILE 79 MET VAL 81 THR LEU 82 PHEASN 76 HIS SER 78 LYS ILE 79 MET VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78LYS ILE 79 MET VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 LYS ILE 79 THRVAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 LYS ILE 79 THR VAL 81 THR LEU 82HIS ASN 76 HIS SER 78 LYS ILE 79 THR VAL 81 THR LEU 82 TYR ASN 76 HISSER 78 LYS ILE 79 VAL VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 LYS ILE 79VAL VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 LYS ILE 79 VAL VAL 81 THRLEU 82 TYR ASN 76 HIS SER 78 TYR ILE 79 LEU VAL 81 THR LEU 82 PHE ASN 76HIS SER 78 TYR ILE 79 LEU VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 TYRILE 79 LEU VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78 TYR ILE 79 MET VAL 81THR LEU 82 PHE ASN 76 HIS SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 HISASN 76 HIS SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 TYR ASN 76 HIS SER 78TYR ILE 79 THR VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 TYR ILE 79 THRVAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 TYR ILE 79 THR VAL 81 THR LEU 82TYR ASN 76 HIS SER 78 TYR ILE 79 VAL VAL 81 THR LEU 82 PHE ASN 76 HISSER 78 TYR ILE 79 VAL VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 TYR ILE 79VAL VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 ASN ILE 79 LEU VAL 81 THRLEU 82 PHE LEU 75 ILE SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75ILE SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 ASNILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 ASN ILE 79 MET VAL 81THR LEU 82 HIS LEU 75 ILE SER 78 ASN ILE 79 MET VAL 81 THR LEU 82 TYRLEU 75 ILE SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78ASN ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 ASN ILE 79 THRVAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82PHE LEU 75 ILE SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 ILESER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 THR ILE 79LEU VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 THR ILE 79 LEU VAL 81 THRLEU 82 HIS LEU 75 ILE SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75ILE SER 78 THR ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 THRILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 THR ILE 79 MET VAL 81THR LEU 82 TYR LEU 75 ILE SER 78 THR ILE 79 THR VAL 81 THR LEU 82 PHELEU 75 ILE SER 78 THR ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78THR ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 THR ILE 79 VALVAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 THR ILE 79 VAL VAL 81 THR LEU 82HIS LEU 75 ILE SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 ILESER 78 ARG ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 ARG ILE 79LEU VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 ARG ILE 79 LEU VAL 81 THRLEU 82 TYR LEU 75 ILE SER 78 ARG ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75ILE SER 78 ARG ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 ARGILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 ARG ILE 79 THR VAL 81THR LEU 82 PHE LEU 75 ILE SER 78 ARG ILE 79 THR VAL 81 THR LEU 82 HISLEU 75 ILE SER 78 ARG ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78ARG ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 ARG ILE 79 VALVAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82TYR LEU 75 ILE SER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILESER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 ASP ILE 79LEU VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 ASP ILE 79 MET VAL 81 THRLEU 82 PHE LEU 75 ILE SER 78 ASP ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75ILE SER 78 ASP ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 ASPILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 ASP ILE 79 THR VAL 81THR LEU 82 HIS LEU 75 ILE SER 78 ASP ILE 79 THR VAL 81 THR LEU 82 TYRLEU 75 ILE SER 78 ASP ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78ASP ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 ASP ILE 79 VALVAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82PHE LEU 75 ILE SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILESER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 GLN ILE 79MET VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 GLN ILE 79 MET VAL 81 THRLEU 82 HIS LEU 75 ILE SER 78 GLN ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75ILE SER 78 GLN ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 GLNILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 GLN ILE 79 THR VAL 81THR LEU 82 TYR LEU 75 ILE SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 PHELEU 75 ILE SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78GLN ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 HIS ILE 79 LEUVAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82HIS LEU 75 ILE SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 ILESER 78 HIS ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 HIS ILE 79MET VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 HIS ILE 79 MET VAL 81 THRLEU 82 TYR LEU 75 ILE SER 78 HIS ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75ILE SER 78 HIS ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 HISILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 HIS ILE 79 VAL VAL 81THR LEU 82 PHE LEU 75 ILE SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 HISLEU 75 ILE SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78LYS ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 LYS ILE 79 LEUVAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 LYS ILE 79 LEU VAL 81 THR LEU 82TYR LEU 75 ILE SER 78 LYS ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILESER 78 LYS ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 LYS ILE 79MET VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 LYS ILE 79 THR VAL 81 THRLEU 82 PHE LEU 75 ILE SER 78 LYS ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75ILE SER 78 LYS ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 LYSILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 LYS ILE 79 VAL VAL 81THR LEU 82 HIS LEU 75 ILE SER 78 LYS ILE 79 VAL VAL 81 THR LEU 82 TYRLEU 75 ILE SER 78 TYR ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78TYR ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 TYR ILE 79 LEUVAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 TYR ILE 79 MET VAL 81 THR LEU 82PHE LEU 75 ILE SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILESER 78 TYR ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 ILE SER 78 TYR ILE 79THR VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 TYR ILE 79 THR VAL 81 THRLEU 82 HIS LEU 75 ILE SER 78 TYR ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75ILE SER 78 TYR ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 TYRILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 TYR ILE 79 VAL VAL 81THR LEU 82 TYR LEU 75 MET SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 PHELEU 75 MET SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET SER 78ASN ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 ASN ILE 79 METVAL 81 THR LEU 82 PHE LEU 75 MET SER 78 ASN ILE 79 MET VAL 81 THR LEU 82HIS LEU 75 MET SER 78 ASN ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 METSER 78 ASN ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 ASN ILE 79THR VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 ASN ILE 79 THR VAL 81 THRLEU 82 TYR LEU 75 MET SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75MET SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 ASNILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 THR ILE 79 LEU VAL 81THR LEU 82 PHE LEU 75 MET SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 HISLEU 75 MET SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 MET SER 78THR ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 THR ILE 79 METVAL 81 THR LEU 82 HIS LEU 75 MET SER 78 THR ILE 79 MET VAL 81 THR LEU 82TYR LEU 75 MET SER 78 THR ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 METSER 78 THR ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 THR ILE 79THR VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 THR ILE 79 VAL VAL 81 THRLEU 82 PHE LEU 75 MET SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75MET SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 ARGILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 ARG ILE 79 LEU VAL 81THR LEU 82 HIS LEU 75 MET SER 78 ARG ILE 79 LEU VAL 81 THR LEU 82 TYRLEU 75 MET SER 78 ARG ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 MET SER 78ARG ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 ARG ILE 79 METVAL 81 THR LEU 82 TYR LEU 75 MET SER 78 ARG ILE 79 THR VAL 81 THR LEU 82PHE LEU 75 MET SER 78 ARG ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 METSER 78 ARG ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 ARG ILE 79VAL VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 ARG ILE 79 VAL VAL 81 THRLEU 82 HIS LEU 75 MET SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75MET SER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 ASPILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 ASP ILE 79 LEU VAL 81THR LEU 82 TYR LEU 75 MET SER 78 ASP ILE 79 MET VAL 81 THR LEU 82 PHELEU 75 MET SER 78 ASP ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 MET SER 78ASP ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 ASP ILE 79 THRVAL 81 THR LEU 82 PHE LEU 75 MET SER 78 ASP ILE 79 THR VAL 81 THR LEU 82HIS LEU 75 MET SER 78 ASP ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 METSER 78 ASP ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 ASP ILE 79VAL VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 ASP ILE 79 VAL VAL 81 THRLEU 82 TYR LEU 75 MET SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75MET SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 GLNILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 GLN ILE 79 MET VAL 81THR LEU 82 PHE LEU 75 MET SER 78 GLN ILE 79 MET VAL 81 THR LEU 82 HISLEU 75 MET SER 78 GLN ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 MET SER 78GLN ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 GLN ILE 79 THRVAL 81 THR LEU 82 HIS LEU 75 MET SER 78 GLN ILE 79 THR VAL 81 THR LEU 82TYR LEU 75 MET SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 METSER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 GLN ILE 79VAL VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 HIS ILE 79 LEU VAL 81 THRLEU 82 PHE LEU 75 MET SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75MET SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 HISILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 HIS ILE 79 MET VAL 81THR LEU 82 HIS LEU 75 MET SER 78 HIS ILE 79 MET VAL 81 THR LEU 82 TYRLEU 75 MET SER 78 HIS ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET SER 78HIS ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 HIS ILE 79 THRVAL 81 THR LEU 82 TYR LEU 75 MET SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82PHE LEU 75 MET SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 METSER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 LYS ILE 79LEU VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 LYS ILE 79 LEU VAL 81 THRLEU 82 HIS LEU 75 MET SER 78 LYS ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75MET SER 78 LYS ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 LYSILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 LYS ILE 79 MET VAL 81THR LEU 82 TYR LEU 75 MET SER 78 LYS ILE 79 THR VAL 81 THR LEU 82 PHELEU 75 MET SER 78 LYS ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 MET SER 78LYS ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 LYS ILE 79 VALVAL 81 THR LEU 82 PHE LEU 75 MET SER 78 LYS ILE 79 VAL VAL 81 THR LEU 82HIS LEU 75 MET SER 78 LYS ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 METSER 78 TYR ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 TYR ILE 79LEU VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 TYR ILE 79 LEU VAL 81 THRLEU 82 TYR LEU 75 MET SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75MET SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 TYRILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 MET SER 78 TYR ILE 79 THR VAL 81THR LEU 82 PHE LEU 75 MET SER 78 TYR ILE 79 THR VAL 81 THR LEU 82 HISLEU 75 MET SER 78 TYR ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 MET SER 78TYR ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 TYR ILE 79 VALVAL 81 THR LEU 82 HIS LEU 75 MET SER 78 TYR ILE 79 VAL VAL 81 THR LEU 82TYR LEU 75 VAL SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 VALSER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 ASN ILE 79LEU VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 ASN ILE 79 MET VAL 81 THRLEU 82 PHE LEU 75 VAL SER 78 ASN ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75VAL SER 78 ASN ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 ASNILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 ASN ILE 79 THR VAL 81THR LEU 82 HIS LEU 75 VAL SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 TYRLEU 75 VAL SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78ASN ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 ASN ILE 79 VALVAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 THR ILE 79 LEU VAL 81 THR LEU 82PHE LEU 75 VAL SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 VALSER 78 THR ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 THR ILE 79MET VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 THR ILE 79 MET VAL 81 THRLEU 82 HIS LEU 75 VAL SER 78 THR ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75VAL SER 78 THR ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 THRILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 THR ILE 79 THR VAL 81THR LEU 82 TYR LEU 75 VAL SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 PHELEU 75 VAL SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78THR ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 ARG ILE 79 LEUVAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 ARG ILE 79 LEU VAL 81 THR LEU 82HIS LEU 75 VAL SER 78 ARG ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 VALSER 78 ARG ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 ARG ILE 79MET VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 ARG ILE 79 MET VAL 81 THRLEU 82 TYR LEU 75 VAL SER 78 ARG ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75VAL SER 78 ARG ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 ARGILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 ARG ILE 79 VAL VAL 81THR LEU 82 PHE LEU 75 VAL SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82 HISLEU 75 VAL SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78ASP ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 ASP ILE 79 LEUVAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 ASP ILE 79 LEU VAL 81 THR LEU 82TYR LEU 75 VAL SER 78 ASP ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VALSER 78 ASP ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 ASP ILE 79MET VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 ASP ILE 79 THR VAL 81 THRLEU 82 PHE LEU 75 VAL SER 78 ASP ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75VAL SER 78 ASP ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 ASPILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 ASP ILE 79 VAL VAL 81THR LEU 82 HIS LEU 75 VAL SER 78 ASP ILE 79 VAL VAL 81 THR LEU 82 TYRLEU 75 VAL SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78GLN ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 GLN ILE 79 LEUVAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 GLN ILE 79 MET VAL 81 THR LEU 82PHE LEU 75 VAL SER 78 GLN ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 VALSER 78 GLN ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 GLN ILE 79THR VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 GLN ILE 79 THR VAL 81 THRLEU 82 HIS LEU 75 VAL SER 78 GLN ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75VAL SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 GLNILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 GLN ILE 79 VAL VAL 81THR LEU 82 TYR LEU 75 VAL SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 PHELEU 75 VAL SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78HIS ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 HIS ILE 79 METVAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 HIS ILE 79 MET VAL 81 THR LEU 82HIS LEU 75 VAL SER 78 HIS ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VALSER 78 HIS ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 HIS ILE 79THR VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 HIS ILE 79 THR VAL 81 THRLEU 82 TYR LEU 75 VAL SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75VAL SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 HISILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 LYS ILE 79 LEU VAL 81THR LEU 82 PHE LEU 75 VAL SER 78 LYS ILE 79 LEU VAL 81 THR LEU 82 HISLEU 75 VAL SER 78 LYS ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78LYS ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 LYS ILE 79 METVAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 LYS ILE 79 MET VAL 81 THR LEU 82TYR LEU 75 VAL SER 78 LYS ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 VALSER 78 LYS ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 LYS ILE 79THR VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 LYS ILE 79 VAL VAL 81 THRLEU 82 PHE LEU 75 VAL SER 78 LYS ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75VAL SER 78 LYS ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 TYRILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 TYR ILE 79 LEU VAL 81THR LEU 82 HIS LEU 75 VAL SER 78 TYR ILE 79 LEU VAL 81 THR LEU 82 TYRLEU 75 VAL SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78TYR ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 VAL SER 78 TYR ILE 79 METVAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 TYR ILE 79 THR VAL 81 THR LEU 82PHE LEU 75 VAL SER 78 TYR ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 VALSER 78 TYR ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 VAL SER 78 TYR ILE 79VAL VAL 81 THR LEU 82 PHE LEU 75 VAL SER 78 TYR ILE 79 VAL VAL 81 THRLEU 82 HIS LEU 75 VAL SER 78 TYR ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75ILE ASN 76 HIS ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HISILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS ILE 79 LEU VAL 81THR LEU 82 TYR LEU 75 ILE ASN 76 HIS ILE 79 MET VAL 81 THR LEU 82 PHELEU 75 ILE ASN 76 HIS ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76HIS ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS ILE 79 THRVAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS ILE 79 THR VAL 81 THR LEU 82HIS LEU 75 ILE ASN 76 HIS ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 ILEASN 76 HIS ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS ILE 79VAL VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS ILE 79 VAL VAL 81 THRLEU 82 TYR LEU 75 MET ASN 76 HIS ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75MET ASN 76 HIS ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HISILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS ILE 79 MET VAL 81THR LEU 82 PHE LEU 75 MET ASN 76 HIS ILE 79 MET VAL 81 THR LEU 82 HISLEU 75 MET ASN 76 HIS ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76HIS ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS ILE 79 THRVAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS ILE 79 THR VAL 81 THR LEU 82TYR LEU 75 MET ASN 76 HIS ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 METASN 76 HIS ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS ILE 79VAL VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS ILE 79 LEU VAL 81 THRLEU 82 PHE LEU 75 VAL ASN 76 HIS ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75VAL ASN 76 HIS ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HISILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS ILE 79 MET VAL 81THR LEU 82 HIS LEU 75 VAL ASN 76 HIS ILE 79 MET VAL 81 THR LEU 82 TYRLEU 75 VAL ASN 76 HIS ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76HIS ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS ILE 79 THRVAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS ILE 79 VAL VAL 81 THR LEU 82PHE LEU 75 VAL ASN 76 HIS ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 VALASN 76 HIS ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78ASN VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASN VAL 81 THRLEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASN VAL 81 THR LEU 82 TYR LEU 75ILE ASN 76 HIS SER 78 THR VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HISSER 78 THR VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 THR VAL 81THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ARG VAL 81 THR LEU 82 PHELEU 75 ILE ASN 76 HIS SER 78 ARG VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76HIS SER 78 ARG VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ASPVAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASP VAL 81 THR LEU 82HIS LEU 75 ILE ASN 76 HIS SER 78 ASP VAL 81 THR LEU 82 TYR LEU 75 ILEASN 76 HIS SER 78 GLN VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78GLN VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 GLN VAL 81 THRLEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 HIS VAL 81 THR LEU 82 PHE LEU 75ILE ASN 76 HIS SER 78 HIS VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HISSER 78 HIS VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 LYS VAL 81THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 LYS VAL 81 THR LEU 82 HISLEU 75 ILE ASN 76 HIS SER 78 LYS VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76HIS SER 78 TYR VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 TYRVAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 TYR VAL 81 THR LEU 82TYR LEU 75 MET ASN 76 HIS SER 78 ASN VAL 81 THR LEU 82 PHE LEU 75 METASN 76 HIS SER 78 ASN VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78ASN VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 THR VAL 81 THRLEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 THR VAL 81 THR LEU 82 HIS LEU 75MET ASN 76 HIS SER 78 THR VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HISSER 78 ARG VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ARG VAL 81THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ARG VAL 81 THR LEU 82 TYRLEU 75 MET ASN 76 HIS SER 78 ASP VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76HIS SER 78 ASP VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASPVAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 GLN VAL 81 THR LEU 82PHE LEU 75 MET ASN 76 HIS SER 78 GLN VAL 81 THR LEU 82 HIS LEU 75 METASN 76 HIS SER 78 GLN VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78HIS VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 HIS VAL 81 THRLEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 HIS VAL 81 THR LEU 82 TYR LEU 75MET ASN 76 HIS SER 78 LYS VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HISSER 78 LYS VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 LYS VAL 81THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 TYR VAL 81 THR LEU 82 PHELEU 75 MET ASN 76 HIS SER 78 TYR VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76HIS SER 78 TYR VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASNVAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASN VAL 81 THR LEU 82HIS LEU 75 VAL ASN 76 HIS SER 78 ASN VAL 81 THR LEU 82 TYR LEU 75 VALASN 76 HIS SER 78 THR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78THR VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 THR VAL 81 THRLEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ARG VAL 81 THR LEU 82 PHE LEU 75VAL ASN 76 HIS SER 78 ARG VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HISSER 78 ARG VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASP VAL 81THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASP VAL 81 THR LEU 82 HISLEU 75 VAL ASN 76 HIS SER 78 ASP VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76HIS SER 78 GLN VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 GLNVAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 GLN VAL 81 THR LEU 82TYR LEU 75 VAL ASN 76 HIS SER 78 HIS VAL 81 THR LEU 82 PHE LEU 75 VALASN 76 HIS SER 78 HIS VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78HIS VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 LYS VAL 81 THRLEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 LYS VAL 81 THR LEU 82 HIS LEU 75VAL ASN 76 HIS SER 78 LYS VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HISSER 78 TYR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 TYR VAL 81THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 TYR VAL 81 THR LEU 82 TYRLEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 LEU LEU 82 PHE LEU 75 ILE ASN 76HIS SER 78 ASN ILE 79 LEU LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASNILE 79 LEU LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 MET LEU 82PHE LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 MET LEU 82 HIS LEU 75 ILEASN 76 HIS SER 78 ASN ILE 79 MET LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78ASN ILE 79 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 THRLEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 THR LEU 82 TYR LEU 75ILE ASN 76 HIS SER 78 ASN ILE 79 VAL LEU 82 PHE LEU 75 ILE ASN 76 HISSER 78 ASN ILE 79 VAL LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79VAL LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 LEU LEU 82 PHELEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 LEU LEU 82 HIS LEU 75 ILE ASN 76HIS SER 78 THR ILE 79 LEU LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 THRILE 79 MET LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 MET LEU 82HIS LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 MET LEU 82 TYR LEU 75 ILEASN 76 HIS SER 78 THR ILE 79 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78THR ILE 79 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 THRLEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 VAL LEU 82 PHE LEU 75ILE ASN 76 HIS SER 78 THR ILE 79 VAL LEU 82 HIS LEU 75 ILE ASN 76 HISSER 78 THR ILE 79 VAL LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79LEU LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 LEU LEU 82 HISLEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 LEU LEU 82 TYR LEU 75 ILE ASN 76HIS SER 78 ARG ILE 79 MET LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ARGILE 79 MET LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 MET LEU 82TYR LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 THR LEU 82 PHE LEU 75 ILEASN 76 HIS SER 78 ARG ILE 79 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78ARG ILE 79 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 VALLEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 VAL LEU 82 HIS LEU 75ILE ASN 76 HIS SER 78 ARG ILE 79 VAL LEU 82 TYR LEU 75 ILE ASN 76 HISSER 78 ASP ILE 79 LEU LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79LEU LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 LEU LEU 82 TYRLEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 MET LEU 82 PHE LEU 75 ILE ASN 76HIS SER 78 ASP ILE 79 MET LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASPILE 79 MET LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 THR LEU 82PHE LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 THR LEU 82 HIS LEU 75 ILEASN 76 HIS SER 78 ASP ILE 79 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78ASP ILE 79 VAL LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 VALLEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 VAL LEU 82 TYR LEU 75ILE ASN 76 HIS SER 78 GLN ILE 79 LEU LEU 82 PHE LEU 75 ILE ASN 76 HISSER 78 GLN ILE 79 LEU LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79LEU LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 MET LEU 82 PHELEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 MET LEU 82 HIS LEU 75 ILE ASN 76HIS SER 78 GLN ILE 79 MET LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 GLNILE 79 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 THR LEU 82HIS LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 THR LEU 82 TYR LEU 75 ILEASN 76 HIS SER 78 GLN ILE 79 VAL LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78GLN ILE 79 VAL LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 VALLEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 LEU LEU 82 PHE LEU 75ILE ASN 76 HIS SER 78 HIS ILE 79 LEU LEU 82 HIS LEU 75 ILE ASN 76 HISSER 78 HIS ILE 79 LEU LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79MET LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 MET LEU 82 HISLEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 MET LEU 82 TYR LEU 75 ILE ASN 76HIS SER 78 HIS ILE 79 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 HISILE 79 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 THR LEU 82TYR LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 VAL LEU 82 PHE LEU 75 ILEASN 76 HIS SER 78 HIS ILE 79 VAL LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78HIS ILE 79 VAL LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 LEULEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 LEU LEU 82 HIS LEU 75ILE ASN 76 HIS SER 78 LYS ILE 79 LEU LEU 82 TYR LEU 75 ILE ASN 76 HISSER 78 LYS ILE 79 MET LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79MET LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 MET LEU 82 TYRLEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 THR LEU 82 PHE LEU 75 ILE ASN 76HIS SER 78 LYS ILE 79 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 LYSILE 79 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 VAL LEU 82PHE LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 VAL LEU 82 HIS LEU 75 ILEASN 76 HIS SER 78 LYS ILE 79 VAL LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78TYR ILE 79 LEU LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 LEULEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 LEU LEU 82 TYR LEU 75ILE ASN 76 HIS SER 78 TYR ILE 79 MET LEU 82 PHE LEU 75 ILE ASN 76 HISSER 78 TYR ILE 79 MET LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79MET LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 THR LEU 82 PHELEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 THR LEU 82 HIS LEU 75 ILE ASN 76HIS SER 78 TYR ILE 79 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 TYRILE 79 VAL LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 VAL LEU 82HIS LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 VAL LEU 82 TYR LEU 75 METASN 76 HIS SER 78 ASN ILE 79 LEU LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78ASN ILE 79 LEU LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 LEULEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 MET LEU 82 PHE LEU 75MET ASN 76 HIS SER 78 ASN ILE 79 MET LEU 82 HIS LEU 75 MET ASN 76 HISSER 78 ASN ILE 79 MET LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 THR LEU 82 HISLEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 THR LEU 82 TYR LEU 75 MET ASN 76HIS SER 78 ASN ILE 79 VAL LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASNILE 79 VAL LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 VAL LEU 82TYR LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 LEU LEU 82 PHE LEU 75 METASN 76 HIS SER 78 THR ILE 79 LEU LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78THR ILE 79 LEU LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 METLEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 MET LEU 82 HIS LEU 75MET ASN 76 HIS SER 78 THR ILE 79 MET LEU 82 TYR LEU 75 MET ASN 76 HISSER 78 THR ILE 79 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 THR ILE 79THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 THR LEU 82 TYRLEU 75 MET ASN 76 HIS SER 78 THR ILE 79 VAL LEU 82 PHE LEU 75 MET ASN 76HIS SER 78 THR ILE 79 VAL LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 THRILE 79 VAL LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 LEU LEU 82PHE LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 LEU LEU 82 HIS LEU 75 METASN 76 HIS SER 78 ARG ILE 79 LEU LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78ARG ILE 79 MET LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 METLEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 MET LEU 82 TYR LEU 75MET ASN 76 HIS SER 78 ARG ILE 79 THR LEU 82 PHE LEU 75 MET ASN 76 HISSER 78 ARG ILE 79 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 VAL LEU 82 PHELEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 VAL LEU 82 HIS LEU 75 MET ASN 76HIS SER 78 ARG ILE 79 VAL LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASPILE 79 LEU LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 LEU LEU 82HIS LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 LEU LEU 82 TYR LEU 75 METASN 76 HIS SER 78 ASP ILE 79 MET LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78ASP ILE 79 MET LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 METLEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 THR LEU 82 PHE LEU 75MET ASN 76 HIS SER 78 ASP ILE 79 THR LEU 82 HIS LEU 75 MET ASN 76 HISSER 78 ASP ILE 79 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79VAL LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 VAL LEU 82 HISLEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 VAL LEU 82 TYR LEU 75 MET ASN 76HIS SER 78 GLN ILE 79 LEU LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 GLNILE 79 LEU LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 LEU LEU 82TYR LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 MET LEU 82 PHE LEU 75 METASN 76 HIS SER 78 GLN ILE 79 MET LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78GLN ILE 79 MET LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 THRLEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 THR LEU 82 HIS LEU 75MET ASN 76 HIS SER 78 GLN ILE 79 THR LEU 82 TYR LEU 75 MET ASN 76 HISSER 78 GLN ILE 79 VAL LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79VAL LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 VAL LEU 82 TYRLEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 LEU LEU 82 PHE LEU 75 MET ASN 76HIS SER 78 HIS ILE 79 LEU LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 HISILE 79 LEU LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 MET LEU 82PHE LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 MET LEU 82 HIS LEU 75 METASN 76 HIS SER 78 HIS ILE 79 MET LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78HIS ILE 79 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 THRLEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 THR LEU 82 TYR LEU 75MET ASN 76 HIS SER 78 HIS ILE 79 VAL LEU 82 PHE LEU 75 MET ASN 76 HISSER 78 HIS ILE 79 VAL LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79VAL LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 LEU LEU 82 PHELEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 LEU LEU 82 HIS LEU 75 MET ASN 76HIS SER 78 LYS ILE 79 LEU LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 LYSILE 79 MET LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 MET LEU 82HIS LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 MET LEU 82 TYR LEU 75 METASN 76 HIS SER 78 LYS ILE 79 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78LYS ILE 79 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 THRLEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 VAL LEU 82 PHE LEU 75MET ASN 76 HIS SER 78 LYS ILE 79 VAL LEU 82 HIS LEU 75 MET ASN 76 HISSER 78 LYS ILE 79 VAL LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79LEU LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 LEU LEU 82 HISLEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 LEU LEU 82 TYR LEU 75 MET ASN 76HIS SER 78 TYR ILE 79 MET LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 TYRILE 79 MET LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 MET LEU 82TYR LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 THR LEU 82 PHE LEU 75 METASN 76 HIS SER 78 TYR ILE 79 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78TYR ILE 79 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 VALLEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 VAL LEU 82 HIS LEU 75MET ASN 76 HIS SER 78 TYR ILE 79 VAL LEU 82 TYR LEU 75 VAL ASN 76 HISSER 78 ASN ILE 79 LEU LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79LEU LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 LEU LEU 82 TYRLEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 MET LEU 82 PHE LEU 75 VAL ASN 76HIS SER 78 ASN ILE 79 MET LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASNILE 79 MET LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 THR LEU 82PHE LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 THR LEU 82 HIS LEU 75 VALASN 76 HIS SER 78 ASN ILE 79 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78ASN ILE 79 VAL LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 VALLEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 VAL LEU 82 TYR LEU 75VAL ASN 76 HIS SER 78 THR ILE 79 LEU LEU 82 PHE LEU 75 VAL ASN 76 HISSER 78 THR ILE 79 LEU LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79LEU LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 MET LEU 82 PHELEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 MET LEU 82 HIS LEU 75 VAL ASN 76HIS SER 78 THR ILE 79 MET LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 THRILE 79 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 THR LEU 82HIS LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 THR LEU 82 TYR LEU 75 VALASN 76 HIS SER 78 THR ILE 79 VAL LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78THR ILE 79 VAL LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 VALLEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 LEU LEU 82 PHE LEU 75VAL ASN 76 HIS SER 78 ARG ILE 79 LEU LEU 82 HIS LEU 75 VAL ASN 76 HISSER 78 ARG ILE 79 LEU LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79MET LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 MET LEU 82 HISLEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 MET LEU 82 TYR LEU 75 VAL ASN 76HIS SER 78 ARG ILE 79 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ARGILE 79 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 THR LEU 82TYR LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 VAL LEU 82 PHE LEU 75 VALASN 76 HIS SER 78 ARG ILE 79 VAL LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78ARG ILE 79 VAL LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 LEULEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 LEU LEU 82 HIS LEU 75VAL ASN 76 HIS SER 78 ASP ILE 79 LEU LEU 82 TYR LEU 75 VAL ASN 76 HISSER 78 ASP ILE 79 MET LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79MET LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 MET LEU 82 TYRLEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 THR LEU 82 PHE LEU 75 VAL ASN 76HIS SER 78 ASP ILE 79 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASPILE 79 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 VAL LEU 82PHE LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 VAL LEU 82 HIS LEU 75 VALASN 76 HIS SER 78 ASP ILE 79 VAL LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78GLN ILE 79 LEU LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 LEULEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 LEU LEU 82 TYR LEU 75VAL ASN 76 HIS SER 78 GLN ILE 79 MET LEU 82 PHE LEU 75 VAL ASN 76 HISSER 78 GLN ILE 79 MET LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79MET LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 THR LEU 82 PHELEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 THR LEU 82 HIS LEU 75 VAL ASN 76HIS SER 78 GLN ILE 79 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 GLNILE 79 VAL LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 VAL LEU 82HIS LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 VAL LEU 82 TYR LEU 75 VALASN 76 HIS SER 78 HIS ILE 79 LEU LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78HIS ILE 79 LEU LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 LEULEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 MET LEU 82 PHE LEU 75VAL ASN 76 HIS SER 78 HIS ILE 79 MET LEU 82 HIS LEU 75 VAL ASN 76 HISSER 78 HIS ILE 79 MET LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 THR LEU 82 HISLEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 THR LEU 82 TYR LEU 75 VAL ASN 76HIS SER 78 HIS ILE 79 VAL LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 HISILE 79 VAL LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 VAL LEU 82TYR LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 LEU LEU 82 PHE LEU 75 VALASN 76 HIS SER 78 LYS ILE 79 LEU LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78LYS ILE 79 LEU LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 METLEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 MET LEU 82 HIS LEU 75VAL ASN 76 HIS SER 78 LYS ILE 79 MET LEU 82 TYR LEU 75 VAL ASN 76 HISSER 78 LYS ILE 79 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 THR LEU 82 TYRLEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 VAL LEU 82 PHE LEU 75 VAL ASN 76HIS SER 78 LYS ILE 79 VAL LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 LYSILE 79 VAL LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 LEU LEU 82PHE LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 LEU LEU 82 HIS LEU 75 VALASN 76 HIS SER 78 TYR ILE 79 LEU LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78TYR ILE 79 MET LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 METLEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 MET LEU 82 TYR LEU 75VAL ASN 76 HIS SER 78 TYR ILE 79 THR LEU 82 PHE LEU 75 VAL ASN 76 HISSER 78 TYR ILE 79 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 VAL LEU 82 PHELEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 VAL LEU 82 HIS LEU 75 VAL ASN 76HIS SER 78 TYR ILE 79 VAL LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ASNILE 79 LEU VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81THR LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81 THR LEU 75 ILEASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78THR ILE 79 LEU VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 METVAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 75ILE ASN 76 HIS SER 78 THR ILE 79 VAL VAL 81 THR LEU 75 ILE ASN 76 HISSER 78 ARG ILE 79 LEU VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79MET VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 THR VAL 81 THRLEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 VAL VAL 81 THR LEU 75 ILE ASN 76HIS SER 78 ASP ILE 79 LEU VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 ASPILE 79 MET VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 THR VAL 81THR LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 VAL VAL 81 THR LEU 75 ILEASN 76 HIS SER 78 GLN ILE 79 LEU VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78GLN ILE 79 MET VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 THRVAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 VAL VAL 81 THR LEU 75ILE ASN 76 HIS SER 78 HIS ILE 79 LEU VAL 81 THR LEU 75 ILE ASN 76 HISSER 78 HIS ILE 79 MET VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79THR VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 VAL VAL 81 THRLEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 LEU VAL 81 THR LEU 75 ILE ASN 76HIS SER 78 LYS ILE 79 MET VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 LYSILE 79 THR VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 VAL VAL 81THR LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 LEU VAL 81 THR LEU 75 ILEASN 76 HIS SER 78 TYR ILE 79 MET VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78TYR ILE 79 THR VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 VALVAL 81 THR LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 LEU VAL 81 THR LEU 75MET ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81 THR LEU 75 MET ASN 76 HISSER 78 ASN ILE 79 THR VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79VAL VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THRLEU 75 MET ASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THR LEU 75 MET ASN 76HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 THRILE 79 VAL VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 LEU VAL 81THR LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 MET VAL 81 THR LEU 75 METASN 76 HIS SER 78 ARG ILE 79 THR VAL 81 THR LEU 75 MET ASN 76 HIS SER 78ARG ILE 79 VAL VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 LEUVAL 81 THR LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 MET VAL 81 THR LEU 75MET ASN 76 HIS SER 78 ASP ILE 79 THR VAL 81 THR LEU 75 MET ASN 76 HISSER 78 ASP ILE 79 VAL VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79LEU VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 MET VAL 81 THRLEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 THR VAL 81 THR LEU 75 MET ASN 76HIS SER 78 GLN ILE 79 VAL VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 HISILE 79 LEU VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 MET VAL 81THR LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 THR VAL 81 THR LEU 75 METASN 76 HIS SER 78 HIS ILE 79 VAL VAL 81 THR LEU 75 MET ASN 76 HIS SER 78LYS ILE 79 LEU VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 METVAL 81 THR LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 THR VAL 81 THR LEU 75MET ASN 76 HIS SER 78 LYS ILE 79 VAL VAL 81 THR LEU 75 MET ASN 76 HISSER 78 TYR ILE 79 LEU VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79MET VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 THR VAL 81 THRLEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 VAL VAL 81 THR LEU 75 VAL ASN 76HIS SER 78 ASN ILE 79 LEU VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 ASNILE 79 MET VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81THR LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 75 VALASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78THR ILE 79 MET VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 THRVAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 VAL VAL 81 THR LEU 75VAL ASN 76 HIS SER 78 ARG ILE 79 LEU VAL 81 THR LEU 75 VAL ASN 76 HISSER 78 ARG ILE 79 MET VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79THR VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 VAL VAL 81 THRLEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 LEU VAL 81 THR LEU 75 VAL ASN 76HIS SER 78 ASP ILE 79 MET VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 ASPILE 79 THR VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 VAL VAL 81THR LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 LEU VAL 81 THR LEU 75 VALASN 76 HIS SER 78 GLN ILE 79 MET VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78GLN ILE 79 THR VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 VALVAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 LEU VAL 81 THR LEU 75VAL ASN 76 HIS SER 78 HIS ILE 79 MET VAL 81 THR LEU 75 VAL ASN 76 HISSER 78 HIS ILE 79 THR VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79VAL VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 LEU VAL 81 THRLEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 MET VAL 81 THR LEU 75 VAL ASN 76HIS SER 78 LYS ILE 79 THR VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 LYSILE 79 VAL VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 LEU VAL 81THR LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 MET VAL 81 THR LEU 75 VALASN 76 HIS SER 78 TYR ILE 79 THR VAL 81 THR LEU 75 VAL ASN 76 HIS SER 78TYR ILE 79 VAL VAL 81 THR

TABLE 7 Sextuple Substitution Variants LEU 75 ILE ASN 76 HIS SER 78 ASNILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79LEU VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 LEUVAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81 THRLEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81 THR LEU 82TYR LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 PRELEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75ILE ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 ILEASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HISSER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78THR ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 THRILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79LEU VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 METVAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 MET VAL 81THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THRLEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 82PHE LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 82 HISLEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75ILE ASN 76 HIS SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 ILEASN 76 HIS SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76HIS SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HISSER 78 ARG ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78ARG ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ARGILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79MET VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 METVAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 MET VAL 81THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 THR VAL 81 THRLEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 THR VAL 81 THR LEU 82HIS LEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 THR VAL 81 THR LEU 82 TYRLEU 75 ILE ASN 76 HIS SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75ILE ASN 76 HIS SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 ILEASN 76 HIS SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76HIS SER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HISSER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78ASP ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ASPILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79MET VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 METVAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 THR VAL 81THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 THR VAL 81 THRLEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 THR VAL 81 THR LEU 82TYR LEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 VAL VAL 81 THR LEU 82 PHELEU 75 ILE ASN 76 HIS SER 78 ASP ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75ILE ASN 76 HIS SER 78 ASP ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 ILEASN 76 HIS SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76HIS SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HISSER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78GLN ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 GLNILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79MET VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 THRVAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 THR VAL 81THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 THR VAL 81 THRLEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82PHE LEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 HISLEU 75 ILE ASN 76 HIS SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75ILE ASN 76 HIS SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILEASN 76 HIS SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76HIS SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HISSER 78 HIS ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78HIS ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 HISILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79THR VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 THRVAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 THR VAL 81THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 VAL VAL 81 THRLEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82HIS LEU 75 ILE ASN 76 HIS SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 TYRLEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75ILE ASN 76 HIS SER 78 LYS ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILEASN 76 HIS SER 78 LYS ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76HIS SER 78 LYS ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HISSER 78 LYS ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78LYS ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 LYSILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79THR VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 THRVAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 VAL VAL 81THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 VAL VAL 81 THRLEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 LYS ILE 79 VAL VAL 81 THR LEU 82TYR LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 LEU VAL 81 THR LEU 82 PHELEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75ILE ASN 76 HIS SER 78 TYR ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 ILEASN 76 HIS SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76HIS SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HISSER 78 TYR ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78TYR ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 TYRILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79THR VAL 81 THR LEU 82 TYR LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 VALVAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 VAL VAL 81THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 TYR ILE 79 VAL VAL 81 THRLEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82PHE LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 HISLEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75MET ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 METASN 76 HIS SER 78 ASN ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76HIS SER 78 ASN ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HISSER 78 ASN ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78ASN ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASNILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79VAL VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 VALVAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THRLEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82HIS LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 TYRLEU 75 MET ASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75MET ASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 METASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HISSER 78 THR ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78THR ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 THRILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 THR ILE 79VAL VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 VALVAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 LEU VAL 81THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 LEU VAL 81 THRLEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 LEU VAL 81 THR LEU 82TYR LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 MET VAL 81 THR LEU 82 PHELEU 75 MET ASN 76 HIS SER 78 ARG ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75MET ASN 76 HIS SER 78 ARG ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 METASN 76 HIS SER 78 ARG ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76HIS SER 78 ARG ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HISSER 78 ARG ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78ARG ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ARGILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ARG ILE 79VAL VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 LEUVAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 LEU VAL 81THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 LEU VAL 81 THRLEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 MET VAL 81 THR LEU 82PHE LEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 MET VAL 81 THR LEU 82 HISLEU 75 MET ASN 76 HIS SER 78 ASP ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75MET ASN 76 HIS SER 78 ASP ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 METASN 76 HIS SER 78 ASP ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76HIS SER 78 ASP ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HISSER 78 ASP ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78ASP ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASPILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79LEU VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 LEUVAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 LEU VAL 81THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 MET VAL 81 THRLEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 MET VAL 81 THR LEU 82HIS LEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 MET VAL 81 THR LEU 82 TYRLEU 75 MET ASN 76 HIS SER 78 GLN ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75MET ASN 76 HIS SER 78 GLN ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 METASN 76 HIS SER 78 GLN ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76HIS SER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HISSER 78 GLN ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78GLN ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 HISILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79LEU VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 LEUVAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 MET VAL 81THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 MET VAL 81 THRLEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 MET VAL 81 THR LEU 82TYR LEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 THR VAL 81 THR LEU 82 PHELEU 75 MET ASN 76 HIS SER 78 HIS ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75MET ASN 76 HIS SER 78 HIS ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 METASN 76 HIS SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76HIS SER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HISSER 78 HIS ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78LYS ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 LYSILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79LEU VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 METVAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 MET VAL 81THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 MET VAL 81 THRLEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 THR VAL 81 THR LEU 82PHE LEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 THR VAL 81 THR LEU 82 HISLEU 75 MET ASN 76 HIS SER 78 LYS ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75MET ASN 76 HIS SER 78 LYS ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 METASN 76 HIS SER 78 LYS ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76HIS SER 78 LYS ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HISSER 78 TYR ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78TYR ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 TYRILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79MET VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 METVAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 MET VAL 81THR LEU 82 TYR LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 THR VAL 81 THRLEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 THR VAL 81 THR LEU 82HIS LEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 THR VAL 81 THR LEU 82 TYRLEU 75 MET ASN 76 HIS SER 78 TYR ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75MET ASN 76 HIS SER 78 TYR ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75 METASN 76 HIS SER 78 TYR ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76HIS SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HISSER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78ASN ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASNILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79MET VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 METVAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81 THRLEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81 THR LEU 82TYR LEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 PHELEU 75 VAL ASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 HIS LEU 75VAL ASN 76 HIS SER 78 ASN ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75 VALASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HISSER 78 THR ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78THR ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 THRILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79MET VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 THRVAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 THR VAL 81THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 THR VAL 81 THRLEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 VAL VAL 81 THR LEU 82PHE LEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 HISLEU 75 VAL ASN 76 HIS SER 78 THR ILE 79 VAL VAL 81 THR LEU 82 TYR LEU 75VAL ASN 76 HIS SER 78 ARG ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 VALASN 76 HIS SER 78 ARG ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76HIS SER 78 ARG ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HISSER 78 ARG ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78ARG ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ARGILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79THR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 THRVAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 THR VAL 81THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 VAL VAL 81 THRLEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82HIS LEU 75 VAL ASN 76 HIS SER 78 ARG ILE 79 VAL VAL 81 THR LEU 82 TYRLEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75VAL ASN 76 HIS SER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 VALASN 76 HIS SER 78 ASP ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76HIS SER 78 ASP ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HISSER 78 ASP ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78ASP ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASPILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79THR VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 THRVAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 VAL VAL 81THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 VAL VAL 81 THRLEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 ASP ILE 79 VAL VAL 81 THR LEU 82TYR LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 PHELEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75VAL ASN 76 HIS SER 78 GLN ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75 VALASN 76 HIS SER 78 GLN ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76HIS SER 78 GLN ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HISSER 78 GLN ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78GLN ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 GLNILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79THR VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 VALVAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 VAL VAL 81THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 GLN ILE 79 VAL VAL 81 THRLEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82PHE LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 HISLEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 LEU VAL 81 THR LEU 82 TYR LEU 75VAL ASN 76 HIS SER 78 HIS ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 VALASN 76 HIS SER 78 HIS ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76HIS SER 78 HIS ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HISSER 78 HIS ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78HIS ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 HISILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79VAL VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 VALVAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 HIS ILE 79 VAL VAL 81THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 LEU VAL 81 THRLEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 LEU VAL 81 THR LEU 82HIS LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 LEU VAL 81 THR LEU 82 TYRLEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75VAL ASN 76 HIS SER 78 LYS ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 VALASN 76 HIS SER 78 LYS ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76HIS SER 78 LYS ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HISSER 78 LYS ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78LYS ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 LYSILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79VAL VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 LYS ILE 79 VALVAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 LEU VAL 81THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 LEU VAL 81 THRLEU 82 HIS LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 LEU VAL 81 THR LEU 82TYR LEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 PHELEU 75 VAL ASN 76 HIS SER 78 TYR ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75VAL ASN 76 HIS SER 73 TYR ILE 79 MET VAL 81 THR LEU 82 TYR LEU 75 VALASN 76 HIS SER 78 TYR ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76HIS SER 78 TYR ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 VAL ASN 76 HISSER 78 TYR ILE 79 THR VAL 81 THR LEU 82 TYR LEU 75 VAL ASN 76 HIS SER 78TYR ILE 79 VAL VAL 81 THR LEU 82 PHE LEU 75 VAL ASN 76 HIS SER 78 TYRILE 79 VAL VAL 81 THR LEU 82 HIS

TABLE 8 Single Substitution Variants LEU 82 PHE LEU 82 HIS VAL 81 THRILE 79 LEU ILE 79 MET ILE 79 THR SER 78 ASN SER 78 THR ASN 76 HIS LEU 75ILE LEU 75 MET

TABLE 9 Double Substitution Variants VAL 81 THR LEU 82 PHE VAL 81 THRLEU 82 HIS ILE 79 LEU LEU 82 PHE ILE 79 LEU LEU 82 HIS ILE 79 MET LEU 82PHE ILE 79 MET LEU 82 HIS ILE 79 THR LEU 82 PHE ILE 79 THR LEU 82 HISILE 79 LEU VAL 81 THR ILE 79 MET VAL 81 THR ILE 79 THR VAL 81 THR SER 78ASN LEU 82 PHE SER 78 ASN LEU 82 HIS SER 78 THR LEU 82 PHE SER 78 THRLEU 82 HIS SER 78 ASN VAL 81 THR SER 78 THR VAL 81 THR SER 78 ASN ILE 79LEU SER 78 ASN ILE 79 MET SER 78 ASN ILE 79 THR SER 78 THR ILE 79 LEUSER 78 THR ILE 79 MET SER 78 THR ILE 79 THR ASN 76 HIS LEU 82 PHE ASN 76HIS LEU 82 HIS ASN 76 HIS VAL 81 THR ASN 76 HIS ILE 79 LEU ASN 76 HISILE 79 MET ASN 76 HIS ILE 79 THR ASN 76 HIS SER 78 ASN ASN 76 HIS SER 78THR LEU 75 ILE LEU 82 PHE LEU 75 ILE LEU 82 HIS LEU 75 MET LEU 82 PHELEU 75 MET LEU 82 HIS LEU 75 ILE VAL 81 THR LEU 75 MET VAL 81 THR LEU 75ILE ILE 79 LEU LEU 75 ILE ILE 79 MET LEU 75 ILE ILE 79 THR LEU 75 METILE 79 LEU LEU 75 MET ILE 79 MET LEU 75 MET ILE 79 THR LEU 75 ILE SER 78ASN LEU 75 ILE SER 78 THR LEU 75 MET SER 78 ASN LEU 75 MET SER 78 THRLEU 75 ILE ASN 76 HIS LEU 75 MET ASN 76 HIS

TABLE 10 Triple Substitution Variants ILE 79 LEU VAL 81 THR LEU 82 PHEILE 79 LEU VAL 81 THR LEU 82 HIS ILE 79 MET VAL 81 THR LEU 82 PHE ILE 79MET VAL 81 THR LEU 82 HIS ILE 79 THR VAL 81 THR LEU 82 PHE ILE 79 THRVAL 81 THR LEU 82 HIS SER 78 ASN VAL 81 THR LEU 82 PHE SER 78 ASN VAL 81THR LEU 82 HIS SER 78 THR VAL 81 THR LEU 82 PHE SER 78 THR VAL 81 THRLEU 82 HIS SER 78 ASN ILE 79 LEU LEU 82 PHE SER 78 ASN ILE 79 LEU LEU 82HIS SER 78 ASN ILE 79 MET LEU 82 PHE SER 78 ASN ILE 79 MET LEU 82 HISSER 78 ASN ILE 79 THR LEU 82 PHE SER 78 ASN ILE 79 THR LEU 82 HIS SER 78THR ILE 79 LEU LEU 82 PHE SER 78 THR ILE 79 LEU LEU 82 HIS SER 78 THRILE 79 MET LEU 82 PHE SER 78 THR ILE 79 MET LEU 82 HIS SER 78 THR ILE 79THR LEU 82 PHE SER 78 THR ILE 79 THR LEU 82 HIS SER 78 ASN ILE 79 LEUVAL 81 THR SER 78 ASN ILE 79 MET VAL 81 THR SER 78 ASN ILE 79 THR VAL 81THR SER 78 THR ILE 79 LEU VAL 81 THR SER 78 THR ILE 79 MET VAL 81 THRSER 78 THR ILE 79 THR VAL 81 THR ASN 76 HIS VAL 81 THR LEU 82 PHE ASN 76HIS VAL 81 THR LEU 82 HIS ASN 76 HIS ILE 79 LEU LEU 82 PHE ASN 76 HISILE 79 LEU LEU 82 HIS ASN 76 HIS ILE 79 MET LEU 82 PHE ASN 76 HIS ILE 79MET LEU 82 HIS ASN 76 HIS ILE 79 THR LEU 82 PHE ASN 76 HIS ILE 79 THRLEU 82 HIS ASN 76 HIS ILE 79 LEU VAL 81 THR ASN 76 HIS ILE 79 MET VAL 81THR ASN 76 HIS ILE 79 THR VAL 81 THR ASN 76 HIS SER 78 ASN LEU 82 PHEASN 76 HIS SER 78 ASN LEU 82 HIS ASN 76 HIS SER 78 THR LEU 82 PHE ASN 76HIS SER 78 THR LEU 82 HIS ASN 76 HIS SER 78 ASN VAL 81 THR ASN 76 HISSER 78 THR VAL 81 THR ASN 76 HIS SER 78 ASN ILE 79 LEU ASN 76 HIS SER 78ASN ILE 79 MET ASN 76 HIS SER 78 ASN ILE 79 THR ASN 76 HIS SER 78 THRILE 79 LEU ASN 76 HIS SER 78 THR ILE 79 MET ASN 76 HIS SER 78 THR ILE 79THR LEU 75 ILE VAL 81 THR LEU 82 PHE LEU 75 ILE VAL 81 THR LEU 82 HISLEU 75 MET VAL 81 THR LEU 82 PHE LEU 75 MET VAL 81 THR LEU 82 HIS LEU 75ILE ILE 79 LEU LEU 82 PHE LEU 75 ILE ILE 79 LEU LEU 82 HIS LEU 75 ILEILE 79 MET LEU 82 PHE LEU 75 ILE ILE 79 MET LEU 82 HIS LEU 75 ILE ILE 79THR LEU 82 PHE LEU 75 ILE ILE 79 THR LEU 82 HIS LEU 75 MET ILE 79 LEULEU 82 PHE LEU 75 MET ILE 79 LEU LEU 82 HIS LEU 75 MET ILE 79 MET LEU 82PHE LEU 75 MET ILE 79 MET LEU 82 HIS LEU 75 MET ILE 79 THR LEU 82 PHELEU 75 MET ILE 79 THR LEU 82 HIS LEU 75 ILE ILE 79 LEU VAL 81 THR LEU 75ILE ILE 79 MET VAL 81 THR LEU 75 ILE ILE 79 THR VAL 81 THR LEU 75 METILE 79 LEU VAL 81 THR LEU 75 MET ILE 79 MET VAL 81 THR LEU 75 MET ILE 79THR VAL 81 THR LEU 75 ILE SER 78 ASN LEU 82 PHE LEU 75 ILE SER 78 ASNLEU 82 HIS LEU 75 ILE SER 78 THR LEU 82 PHE LEU 75 ILE SER 78 THR LEU 82HIS LEU 75 MET SER 78 ASN LEU 82 PHE LEU 75 MET SER 78 ASN LEU 82 HISLEU 75 MET SER 78 THR LEU 82 PHE LEU 75 MET SER 78 THR LEU 82 HIS LEU 75ILE SER 78 ASN VAL 81 THR LEU 75 ILE SER 78 THR VAL 81 THR LEU 75 METSER 78 ASN VAL 81 THR LEU 75 MET SER 78 THR VAL 81 THR LEU 75 ILE SER 78ASN ILE 79 LEU LEU 75 ILE SER 78 ASN ILE 79 MET LEU 75 ILE SER 78 ASNILE 79 THR LEU 75 ILE SER 78 THR ILE 79 LEU LEU 75 ILE SER 78 THR ILE 79MET LEU 75 ILE SER 78 THR ILE 79 THR LEU 75 MET SER 78 ASN ILE 79 LEULEU 75 MET SER 78 ASN ILE 79 MET LEU 75 MET SER 78 ASN ILE 79 THR LEU 75MET SER 78 THR ILE 79 LEU LEU 75 MET SER 78 THR ILE 79 MET LEU 75 METSER 78 THR ILE 79 THR LEU 75 ILE ASN 76 HIS LEU 82 PHE LEU 75 ILE ASN 76HIS LEU 82 HIS LEU 75 MET ASN 76 HIS LEU 82 PHE LEU 75 MET ASN 76 HISLEU 82 HIS LEU 75 ILE ASN 76 HIS VAL 81 THR LEU 75 MET ASN 76 HIS VAL 81THR LEU 75 ILE ASN 76 HIS ILE 79 LEU LEU 75 ILE ASN 76 HIS ILE 79 METLEU 75 ILE ASN 76 HIS ILE 79 THR LEU 75 MET ASN 76 HIS ILE 79 LEU LEU 75MET ASN 76 HIS ILE 79 MET LEU 75 MET ASN 76 HIS ILE 79 THR LEU 75 ILEASN 76 HIS SER 78 ASN LEU 75 ILE ASN 76 HIS SER 78 THR LEU 75 MET ASN 76HIS SER 78 ASN LEU 75 MET ASN 76 HIS SER 78 THR

TABLE 11 Quadruple Substitution Variants SER 78 ASN ILE 79 LEU VAL 81THR LEU 82 PHE SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 HIS SER 78 ASNILE 79 MET VAL 81 THR LEU 82 PHE SER 78 ASN ILE 79 MET VAL 81 THR LEU 82HIS SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 PHE SER 78 ASN ILE 79 THRVAL 81 THR LEU 82 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 PHE SER 78THR ILE 79 LEU VAL 81 THR LEU 82 HIS SER 78 THR ILE 79 MET VAL 81 THRLEU 82 PHE SER 78 THR ILE 79 MET VAL 81 THR LEU 82 HIS SER 78 THR ILE 79THR VAL 81 THR LEU 82 PHE SER 78 THR ILE 79 THR VAL 81 THR LEU 82 HISASN 76 HIS ILE 79 LEU VAL 81 THR LEU 82 PHE ASN 76 HIS ILE 79 LEU VAL 81THR LEU 82 HIS ASN 76 HIS ILE 79 MET VAL 81 THR LEU 82 PHE ASN 76 HISILE 79 MET VAL 81 THR LEU 82 HIS ASN 76 HIS ILE 79 THR VAL 81 THR LEU 82PHE ASN 76 HIS ILE 79 THR VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 ASNVAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ASN VAL 81 THR LEU 82 HIS ASN 76HIS SER 78 THR VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 THR VAL 81 THRLEU 82 HIS ASN 76 HIS SER 78 ASN ILE 79 LEU LEU 82 PHE ASN 76 HIS SER 78ASN ILE 79 LEU LEU 82 HIS ASN 76 HIS SER 78 ASN ILE 79 MET LEU 82 PHEASN 76 HIS SER 78 ASN ILE 79 MET LEU 82 HIS ASN 76 HIS SER 78 ASN ILE 79THR LEU 82 PHE ASN 76 HIS SER 78 ASN ILE 79 THR LEU 82 HIS ASN 76 HISSER 78 THR ILE 79 LEU LEU 82 PHE ASN 76 HIS SER 78 THR ILE 79 LEU LEU 82HIS ASN 76 HIS SER 78 THR ILE 79 MET LEU 82 PHE ASN 76 HIS SER 78 THRILE 79 MET LEU 82 HIS ASN 76 HIS SER 78 THR ILE 79 THR LEU 82 PHE ASN 76HIS SER 78 THR ILE 79 THR LEU 82 HIS ASN 76 HIS SER 78 ASN ILE 79 LEUVAL 81 THR ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81 THR ASN 76 HIS SER 78ASN ILE 79 THR VAL 81 THR ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THRASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THR ASN 76 HIS SER 78 THR ILE 79THR VAL 81 THR LEU 75 ILE ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILEILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILE ILE 79 MET VAL 81 THR LEU 82PHE LEU 75 ILE ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILE ILE 79 THRVAL 81 THR LEU 82 PHE LEU 75 ILE ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75MET ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET ILE 79 LEU VAL 81 THRLEU 82 HIS LEU 75 MET ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 MET ILE 79MET VAL 81 THR LEU 82 HIS LEU 75 MET ILE 79 THR VAL 81 THR LEU 82 PHELEU 75 MET ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 ASN VAL 81THR LEU 82 PHE LEU 75 ILE SER 78 ASN VAL 81 THR LEU 82 HIS LEU 75 ILESER 78 THR VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 THR VAL 81 THR LEU 82HIS LEU 75 MET SER 78 ASN VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 ASNVAL 81 THR LEU 82 HIS LEU 75 MET SER 78 THR VAL 81 THR LEU 82 PHE LEU 75MET SER 78 THR VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 ASN ILE 79 LEULEU 82 PHE LEU 75 ILE SER 78 ASN ILE 79 LEU LEU 82 HIS LEU 75 ILE SER 78ASN ILE 79 MET LEU 82 PHE LEU 75 ILE SER 78 ASN ILE 79 MET LEU 82 HISLEU 75 ILE SER 78 ASN ILE 79 THR LEU 82 PHE LEU 75 ILE SER 78 ASN ILE 79THR LEU 82 HIS LEU 75 ILE SER 78 THR ILE 79 LEU LEU 82 PHE LEU 75 ILESER 78 THR ILE 79 LEU LEU 82 HIS LEU 75 ILE SER 78 THR ILE 79 MET LEU 82PHE LEU 75 ILE SER 78 THR ILE 79 MET LEU 82 HIS LEU 75 ILE SER 78 THRILE 79 THR LEU 82 PHE LEU 75 ILE SER 78 THR ILE 79 THR LEU 82 HIS LEU 75MET SER 78 ASN ILE 79 LEU LEU 82 PHE LEU 75 MET SER 78 ASN ILE 79 LEULEU 82 HIS LEU 75 MET SER 78 ASN ILE 79 MET LEU 82 PHE LEU 75 MET SER 78ASN ILE 79 MET LEU 82 HIS LEU 75 MET SER 78 ASN ILE 79 THR LEU 82 PHELEU 75 MET SER 78 ASN ILE 79 THR LEU 82 HIS LEU 75 MET SER 78 THR ILE 79LEU LEU 82 PHE LEU 75 MET SER 78 THR ILE 79 LEU LEU 82 HIS LEU 75 METSER 78 THR ILE 79 MET LEU 82 PHE LEU 75 MET SER 78 THR ILE 79 MET LEU 82HIS LEU 75 MET SER 78 THR ILE 79 THR LEU 82 PHE LEU 75 MET SER 78 THRILE 79 THR LEU 82 HIS LEU 75 ILE SER 78 ASN ILE 79 LEU VAL 81 THR LEU 75ILE SER 78 ASN ILE 79 MET VAL 81 THR LEU 75 ILE SER 78 ASN ILE 79 THRVAL 81 THR LEU 75 ILE SER 78 THR ILE 79 LEU VAL 81 THR LEU 75 ILE SER 78THR ILE 79 MET VAL 81 THR LEU 75 ILE SER 78 THR ILE 79 THR VAL 81 THRLEU 75 MET SER 78 ASN ILE 79 LEU VAL 81 THR LEU 75 MET SER 78 ASN ILE 79MET VAL 81 THR LEU 75 MET SER 78 ASN ILE 79 THR VAL 81 THR LEU 75 METSER 78 THR ILE 79 LEU VAL 81 THR LEU 75 MET SER 78 THR ILE 79 MET VAL 81THR LEU 75 MET SER 78 THR ILE 79 THR VAL 81 THR LEU 75 ILE ASN 76 HISVAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS VAL 81 THR LEU 82 HIS LEU 75MET ASN 76 HIS VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS VAL 81 THRLEU 82 HIS LEU 75 ILE ASN 76 HIS ILE 79 LEU LEU 82 PHE LEU 75 ILE ASN 76HIS ILE 79 LEU LEU 82 HIS LEU 75 ILE ASN 76 HIS ILE 79 MET LEU 82 PHELEU 75 ILE ASN 76 HIS ILE 79 MET LEU 82 HIS LEU 75 ILE ASN 76 HIS ILE 79THR LEU 82 PHE LEU 75 ILE ASN 76 HIS ILE 79 THR LEU 82 HIS LEU 75 METASN 76 HIS ILE 79 LEU LEU 82 PHE LEU 75 MET ASN 76 HIS ILE 79 LEU LEU 82HIS LEU 75 MET ASN 76 HIS ILE 79 MET LEU 82 PHE LEU 75 MET ASN 76 HISILE 79 MET LEU 82 HIS LEU 75 MET ASN 76 HIS ILE 79 THR LEU 82 PHE LEU 75MET ASN 76 HIS ILE 79 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS ILE 79 LEUVAL 81 THR LEU 75 ILE ASN 76 HIS ILE 79 MET VAL 81 THR LEU 75 ILE ASN 76HIS ILE 79 THR VAL 81 THR LEU 75 MET ASN 76 HIS ILE 79 LEU VAL 81 THRLEU 75 MET ASN 76 HIS ILE 79 MET VAL 81 THR LEU 75 MET ASN 76 HIS ILE 79THR VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 ASN LEU 82 PHE LEU 75 ILEASN 76 HIS SER 78 ASN LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 THR LEU 82PHE LEU 75 ILE ASN 76 HIS SER 78 THR LEU 82 HIS LEU 75 MET ASN 76 HISSER 78 ASN LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASN LEU 82 HIS LEU 75MET ASN 76 HIS SER 78 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 THRLEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASN VAL 81 THR LEU 75 ILE ASN 76HIS SER 78 THR VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 ASN VAL 81 THRLEU 75 MET ASN 76 HIS SER 78 THR VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78ASN ILE 79 LEU LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 MET LEU 75 ILEASN 76 HIS SER 78 ASN ILE 79 THR LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79LEU LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 MET LEU 75 ILE ASN 76 HISSER 78 THR ILE 79 THR LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 LEU LEU 75MET ASN 76 HIS SER 78 ASN ILE 79 MET LEU 75 MET ASN 76 HIS SER 78 ASNILE 79 THR LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 LEU LEU 75 MET ASN 76HIS SER 78 THR ILE 79 MET LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 THR

TABLE 12 Quintuple Substitution Variants ASN 76 HIS SER 78 ASN ILE 79LEU VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ASN ILE 79 LEU VAL 81 THRLEU 82 HIS ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81 THR LEU 82 PHE ASN 76HIS SER 78 ASN ILE 79 MET VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 ASNILE 79 THR VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81THR LEU 82 HIS ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 PHEASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 HIS ASN 76 HIS SER 78THR ILE 79 MET VAL 81 THR LEU 82 PHE ASN 76 HIS SER 78 THR ILE 79 METVAL 81 THR LEU 82 HIS ASN 76 HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 82PHE ASN 76 HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 ILESER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 ASN ILE 79LEU VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 ASN ILE 79 MET VAL 81 THRLEU 82 PHE LEU 75 ILE SER 78 ASN ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75ILE SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 ASNILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 THR ILE 79 LEU VAL 81THR LEU 82 PHE LEU 75 ILE SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 HISLEU 75 ILE SER 78 THR ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILE SER 78THR ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILE SER 78 THR ILE 79 THRVAL 81 THR LEU 82 PHE LEU 75 ILE SER 78 THR ILE 79 THR VAL 81 THR LEU 82HIS LEU 75 MET SER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 METSER 78 ASN ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 ASN ILE 79MET VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 ASN ILE 79 MET VAL 81 THRLEU 82 HIS LEU 75 MET SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75MET SER 78 ASN ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 MET SER 78 THRILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 THR ILE 79 LEU VAL 81THR LEU 82 HIS LEU 75 MET SER 78 THR ILE 79 MET VAL 81 THR LEU 82 PHELEU 75 MET SER 78 THR ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 MET SER 78THR ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET SER 78 THR ILE 79 THRVAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS ILE 79 LEU VAL 81 THR LEU 82PHE LEU 75 ILE ASN 76 HIS ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 ILEASN 76 HIS ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS ILE 79MET VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS ILE 79 THR VAL 81 THRLEU 82 PHE LEU 75 ILE ASN 76 HIS ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75MET ASN 76 HIS ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HISILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS ILE 79 MET VAL 81THR LEU 82 PHE LEU 75 MET ASN 76 HIS ILE 79 MET VAL 81 THR LEU 82 HISLEU 75 MET ASN 76 HIS ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76HIS ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASNVAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASN VAL 81 THR LEU 82HIS LEU 75 ILE ASN 76 HIS SER 78 THR VAL 81 THR LEU 82 PHE LEU 75 ILEASN 76 HIS SER 78 THR VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78ASN VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASN VAL 81 THRLEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 THR VAL 81 THR LEU 82 PHE LEU 75MET ASN 76 HIS SER 78 THR VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HISSER 78 ASN ILE 79 LEU LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79LEU LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 MET LEU 82 PHELEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 MET LEU 82 HIS LEU 75 ILE ASN 76HIS SER 78 ASN ILE 79 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASNILE 79 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 LEU LEU 82PHE LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 LEU LEU 82 HIS LEU 75 ILEASN 76 HIS SER 78 THR ILE 79 MET LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78THR ILE 79 MET LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 THRLEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 THR LEU 82 HIS LEU 75MET ASN 76 HIS SER 78 ASN ILE 79 LEU LEU 82 PHE LEU 75 MET ASN 76 HISSER 78 ASN ILE 79 LEU LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79MET LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 MET LEU 82 HISLEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 THR LEU 82 PHE LEU 75 MET ASN 76HIS SER 78 ASN ILE 79 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 THRILE 79 LEU LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 LEU LEU 82HIS LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 MET LEU 82 PHE LEU 75 METASN 76 HIS SER 78 THR ILE 79 MET LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78THR ILE 79 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 THRLEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 LEU VAL 81 THR LEU 75ILE ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81 THR LEU 75 ILE ASN 76 HISSER 78 ASN ILE 79 THR VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79LEU VAL 81 THR LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THRLEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 75 MET ASN 76HIS SER 78 ASN ILE 79 LEU VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 ASNILE 79 MET VAL 81 THR LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81THR LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 75 METASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THR LEU 75 MET ASN 76 HIS SER 78THR ILE 79 THR VAL 81 THR

TABLE 13 Sextuple Substitution Variants LEU 75 ILE ASN 76 HIS SER 78 ASNILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79LEU VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 METVAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 MET VAL 81THR LEU 82 HIS LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81 THRLEU 82 PHE LEU 75 ILE ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81 THR LEU 82HIS LEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 PHELEU 75 ILE ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75ILE ASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75 ILEASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 ILE ASN 76HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 ILE ASN 76 HISSER 78 THR ILE 79 THR VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78ASN ILE 79 LEU VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASNILE 79 LEU VAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79MET VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 METVAL 81 THR LEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81THR LEU 82 PHE LEU 75 MET ASN 76 HIS SER 78 ASN ILE 79 THR VAL 81 THRLEU 82 HIS LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82PHE LEU 75 MET ASN 76 HIS SER 78 THR ILE 79 LEU VAL 81 THR LEU 82 HISLEU 75 MET ASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THR LEU 82 PHE LEU 75MET ASN 76 HIS SER 78 THR ILE 79 MET VAL 81 THR LEU 82 HIS LEU 75 METASN 76 HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 82 PHE LEU 75 MET ASN 76HIS SER 78 THR ILE 79 THR VAL 81 THR LEU 82 HIS

One or more additional substitution mutations (“stabilizingsubstitutions”) outside the epitope region may additionally be made inorder to, for example, restabilize the protease upon mutation of theepitope region or to enhance the proteolytic activity of the variant.Many such stabilizing mutations are well known in the art. Examples ofsuch stabilizing mutations are disclosed in, for example, WO 95/10591,Baeck et al., published Apr. 20, 1995; U.S. Pat. No. 4,914,031, Zukowskiet al., issued Apr. 3, 1990; U.S. Pat. No. 5,470,733, Bryan et al.,issued Nov. 28, 1995; U.S. Pat. No. 5,567,601, Bryan et al., issued Oct.22, 1996; WO 89/07642, U.S. Pat. No. 5,707,848, Bryan et al., issuedJan. 13, 1998; Van Eekelen et al., published Aug. 24, 1989; WO 87/04461,Stabinsky et al., published Jul. 30, 1987; U.S. Pat. No. 4,760,025,Estell et al., issued Jul. 26, 1988; WO 92/11348, Branner et al.,published Jul. 9, 1992; EP 0,405,901, Casteleijn et al., published Jan.2, 1991; WO 91/00345, Branner et al., published Jan. 10, 1991; and WO94/10020, Brode et al., published Mar. 23, 1995.

Preferred stabilizing mutations include one or more of: 1107V; K213R;Y217L; Y217K; N218S; G169A; M50F; Q19E; P5A; S9A; I31L; E156S; G169A;N212G; S188P; T254A; S3C+Q206C; and Q271E. The more preferredstabilizing mutations include one or more of P5A; S9A; I31L; E156S;G169A; N212G; S188P; T254A; S3C+Q206C; Q271E; Y217L; and Y217K. The mostpreferred stabilizing mutations include Y217L and Y217K.

A preferred variant for use in personal care compositions is Δ75-83,Y217L.

Method of Making

The variants are prepared by mutating the nucleotide sequences that codefor a wild-type serine protease, thereby resulting in variants havingmodified amino acid sequences. Such methods are well-known in the art;one such method is set forth below:

A phagemid (pSS-5) containing the wild-type subtilisin BPN′ gene(Mitchison, C. and J. A. Wells, “Protein Engineering of Disulfide Bondsin Subtilisin BPN′”, Biochemistry, Vol. 28, pp. 4807-4815 (1989) istransformed into Escherichia coli dut-ung- strain CJ236 and a singlestranded uracil-containing DNA template is produced using the VCSM13helper phage (Kunkel et al., “Rapid and Efficient Site-SpecificMutagenesis Without Phenotypic Selection”, Methods in Enzymology, Vol154, pp. 367-382 (1987), as modified by Yuckenberg et al.,“Site-Directed in vitro Mutagenesis Using Uracil-Containing DNA andPhagemid Vectors”, Directed Mutagenesis—A Practical Approach, McPherson,M. J. ed., pp. 27-48 (1991). Primer site-directed mutagenesis modifiedfrom the method of Zoller and Smith (Zoller, M. J., and M. Smith,“Oligonucleotide—Directed Mutagenesis Using M13—Derived Vectors: AnEfficient and General Procedure for the Production of Point Mutations inany Fragment of DNA”, Nucleic Acids Research, Vol. 10, pp. 6487-6500(1982) is used to produce all mutants (essentially as presented byYuckenberg et al., supra).

Oligonucleotides are made using a 380B DNA synthesizer (AppliedBiosystems Inc.). Mutagenesis reaction products are transformed intoEscherichia coli strain MM294 (American Type Culture Collection E. coli33625). All mutations are confirmed by DNA sequencing and the isolatedDNA is transformed into the Bacillus subtilis expression strain PG632(Saunders et al., “Optimization of the Signal-Sequence Cleavage Site forSecretion from Bacillus subtilis of a 34-amino acid Fragment of HumanParathyroid Hormone”, Gene, Vol. 102, pp. 277-282 (1991) and Yang etal., “Cloning of the Neutral Protease Gene of Bacillus subtilis and theUse of the Cloned Gene to Create an in vitro-Derived Deletion Mutation”,Journal of Bacteriology, Vol. 160, pp. 15-21 (1984). Preliminaryassessment of variant activity is determined by the ability of PG632cells transformed with mutant plasmids to hydrolyze casein.

Fermentation is as follows. Bacillus subtilis cells (PG632) containingthe variant of interest are grown to mid-log phase in one liter of LBbroth containing 10 g/L glucose, and inoculated into a Biostat Cfermentor (Braun Biotech, Inc., Allentown, Pa.) in a total volume of 9liters. The fermentation medium contains yeast extract, caseinhydrosylate, soluble—partially hydrolyzed starch (Maltrin M-250),antifoarm, buffers, and trace minerals (see “Biology of Bacilli:Applications to Industry”, Doi, R. H. and M. McGloughlin, eds. (1992)).The broth is kept at a constant pH of 7.5 during the fermentation run.Kanamycin (50 g/mL) is added for antibiotic selection of the mutagenizedplasmid. The cells are grown for 18 hours at 37 ° C. to an A₆₀₀ of about60 and the product harvested.

The fermentation broth is taken through the following steps to obtainpure variant. The broth is cleared of Bacillus subtilis cells bytangential flow against a 0.16 μm membrane. The cell-free broth is thenconcentrated by ultrafiltration with a 8000 molecular weight cut-offmembrane. The pH is adjusted to 5.5 with concentrated MES buffer(2-(N-morpholino)ethanesulfonic acid). The variant is further purifiedby cation exchange chromatography with S-sepharose and elution with NaClgradients. (see Scopes, R. K., “Protein Purification Principles andPractice”, Springer-Verlag, New York (1984).

A pNA assay (DelMar et al., Analytical Biochemistry, Vol. 99, pp.316-320 (1979)) is used to determine the active variant concentrationfor fractions collected during gradient elution. This assay measures therate at which p-nitroaniline is released as the variant hydrolyzes thesoluble synthetic substrate,succinyl-alanine-alanine-proline-phenylalanine-p-nitroaniline(sAAPF-pNA). The rate of production of yellow color from the hydrolysisreaction is measured at 410 nm on a spectrophotometer and isproportional to the active enzyme concentration. In addition, absorbancemeasurements at 280 nm are used to determine the total proteinconcentration. The active enzyme/total-protein ratio gives the variantpurity, and is used to identify fractions to be pooled for the stocksolution.

To avoid autolysis of the variant during storage, an equal weight ofpropylene glycol is added to the pooled fractions obtained from thechromatography column. Upon completion of the purification procedure thepurity of the stock variant solution is checked with SDS-PAGE (sodiumdodecyl sulfate polyacrylamide gel electrophoresis) and the absoluteenzyme concentration is determined via an active site titration methodusing trypsin inhibitor type II-T: turkey egg white (Sigma ChemicalCompany, St. Louis, Mo.).

In preparation for use, the enzyme stock solution is eluted through aSephadex-G25 (Pharmacia, Piscataway, N.J.) size exclusion column toremove the propylene glycol and exchange the buffer. The MES buffer inthe enzyme stock solution is exchanged for 0.1 M tris buffer(tris(hydroxymethyl-aminomethane) containing 0.0M CaCl₂ and pH adjustedto 8.6 with HCl. All experiments are carried out at pH 8.6 in trisbuffer thermostated at 25 ° C.

Analytical Methods

The present variants may be tested for enzymatic activity and immuneand/or allergenic response using the following methods, both of whichare known to one skilled in the art. Alternatively, other methodswell-known in the art may be used.

Variant Activity

The protease activity of a variant of the present invention may beassayed by methods which are well-known in the art. Two such methods areset forth herein below:

Skin Flake Activity Method

Using Scotch® #3750G tape, human skin flakes are stripped from the legsof a subject repeatedly until the tape is substantially opaque withflakes. The tape is then cut into 1 inch by 1 inch squares and setaside. In a 10 mm by 35 mm petri dish, 2 mL of 0.75 mg/mL of a controlenzyme (for example, subtilisin BPN′) or the variant to be tested isadded in 0.01 M KH₂PO₄ pH 5.5 buffer. To this solution 1 mL of 2.5%sodium laurate pH 8.6 solution is added. The solution is gently mixed ona platform shaker. The previously prepared tape square is soaked in thesolution (flake side up) for ten minutes continuing gentle mixing. Thetape square is then rinsed gently in tap water for fifteen seconds.Stevenel Blue Stain (3 mL, commercially available from Sigma ChemicalCo., St. Louis, Mo.) is pipetted into a clean petri dish. The rinsedtape square is placed into the stain for three minutes (flake side up)with gentle mixing. The tape square is removed from the stain and rinsedconsecutively in two beakers of 300 mL distilled water, for fifteenseconds per rinse. The tape square is allowed to air-dry. The colorintensity between the tape square obtained from the control enzyme andthe tape square obtained from the variant is compared visually or byusing a chromameter. Relative to the control enzyme tape square, avariant tape square showing less color intensity is indicative of avariant having higher activity.

Dyed Collagen Activity Method

Combine 50 mL of 0.1 M tris buffer (tris-hydroxymethyl-aminomethane)containing 0.01 M CaCl₂ to give pH 8.6, and 0.5 g azocoll (azo dyeimpregnated collagen, commercially available from Sigma Chemical Co.,St. Louis, Mo.). Incubate this mixture at 25 ° C. while gently mixingwith a platform shaker. Filter 2 mL of the mixture through a 0.2 micronsyringe filter and read absorbance of the mixture at 520 nm to zero aspectrophotometer. Add 1 ppm of a control enzyme (for example,subtilisin BPN′) or the variant to be tested to the remaining 48 mL oftris/azocoll mixture. Filter 2 mL of the control/variant containingsolution through a 0.2 micron syringe filter every two minutes for atotal of ten minutes. For each filtered sample, read the absorbanceimmediately at 520 run. Plot the results against time. The slopes of thecontrol and the test conjugate are indicative of relative activities ofthe samples. A higher slope is indicative of a higher activity. The testvariant activity (slope) may be expressed as a percent of the controlactivity (slope).

T-Cell Proliferation Assay

The immune and/or allergenic potential of the variants of the presentinvention may be determined using a T-cell proliferation assay such asthe assay presented hereinbelow. This assay is a variation of the assaydisclosed in Bungy Poor Fard et al., “T Cell Epitopes of the MajorFraction of Rye Grass Lolium perenne (Lol p I) Defined Using OverlappingPeptides in vitro and in vivo”, Clinical Experimental Immunology, Vol.94, pp. 111-116(1993).

The blood of subjects allergic to subtilisin BPN′(prick test positive)and control subjects (prick test negative) are used in this assay. Blood(˜60 mL) from each subject is collected and mononuclear cells areharvested using ficoll-hypaque (which may be obtained from Pharmacia,Piscataway, N.J.). The cells are washed twice in RPMI 1640 (which may beobtained from Gibco, Grand Island, N.Y.) and then resuspended incomplete medium RPMI supplemented with 10% human AB-serumn, 2 mML-glutamine, and 25 μg/mL gentamicin (which may be obtained from Gibco).Cells are cultured at a concentration of 2×10⁵ cells/well in 0.2 mL ofcomplete medium in U-bottomed 96-well microtiter plates. The potentialantigen to be tested (either inactivated BPN′ as positive control or avariant of the present invention is added at a final concentration up toabout 40 μg/mL. Cultures are incubated at 37° C. in 5% CO₂. After fivedays, 1 μCi/well of methyl-³H-thymidine is added and 18 hours later thecells are harvested. ³H-thymidine incorporation by the cell is assessedas a measure of T-cell proliferation by liquid scintillation counting.

Compositions of the Present Invention

The variants herein can be used in any application which is suitable forthe respective wild-type protease. One such example includes cleaningcompositions. Because of the desirable reduced allergenicity and/orimmunogenicity properties of the present variants, the variants mayfurther be used in applications which have minimally benefitted from theuse of proteases. Examples of such applications include those in whichthe variant necessarily comes in close contact with human skin, such aswith the use of personal care compositions.

Cleaning Compositions

The variants may be utilized in cleaning compositions including, but notlimited to, laundry compositions, hard surface cleansing compositions,light duty cleaning compositions including dish cleansing compositions,and automatic dishwasher detergent compositions.

The cleaning compositions herein comprise an effective amount of one ormore variants of the present invention and a cleaning compositioncarrier.

As used herein, “effective amount of variant”, or the like, refers tothe quantity of variant necessary to achieve the proteolytic activitynecessary in the specific cleaning composition. Such effective amountsare readily ascertained by one of ordinary skill in the art and is basedon many factors, such as the particular variant used, the cleaningapplication, the specific composition of the cleaning composition, andwhether a liquid or dry (e.g., granular, bar) composition is desired,and the like. Preferably, the cleaning compositions comprise from about0.0001% to about 10%, more preferably from about 0.001% to about 1%, andmost preferably from about 0.01% to about 0.1% of one or more variantsof the present invention. Several examples of various cleaningcompositions wherein the variants may be employed are discussed infurther detail below.

In addition to the present variants, the present cleaning compositionsfurther comprise a cleaning composition carrier comprising one or morecleaning composition materials compatible with the variant. The term“cleaning composition material”, as used herein, means any materialselected for the particular type of cleaning composition desired and theform of the product (e.g., liquid, granule, bar, spray, stick, paste,gel), which materials are also compatible with the variant used in thecomposition. The specific selection of cleaning composition materials isreadily made by considering the material to be cleaned, the desired formof the composition for the cleaning condition during use. The term“compatible”, as used herein, means the cleaning composition materialsdo not reduce the proteolytic activity of the variant to such an extentthat the variant is not effective as desired during normal usesituations. Specific cleaning composition materials are exemplified indetail hereinafter.

The variants of the present invention may be used in a variety ofdetergent compositions where high sudsing and good cleansing activity isdesired. Thus, the variants can be used with various conventionalingredients to provide fully-formulated hard-surface cleaners,dishwashing compositions, fabric laundering compositions, and the like.Such compositions can be in the form of liquids, granules, bars, and thelike. Such compositions can be formulated as “concentrated” detergentswhich contain as much as from about 30% to about 60% by weight ofsurfactants.

The cleaning compositions herein may optionally, and preferably, containvarious surfactants (e.g., anionic, nonionic, or zwitterionicsurfactants). Such surfactants are typically present at levels of fromabout 5% to about 35% of the compositions.

Nonlimiting examples of surfactants useful herein include theconventional C₁₁-C₁₈ alkyl benzene sulfonates and primary and randomalkyl sulfates, the C₁₀-C₁₈ secondary (2,3) alkyl sulfates of theformulas CH₃(CH₂)_(x)(CHOSO₃)⁻M^(+)CH) ₃ and CH₃(CH₂)_(y)(CHOSO₃ ⁻M+)CH₂CH₃ wherein x and (y+1) are integers of at least about 7, preferablyat least about 9, and M is a water-solubilizing cation, especiallysodium, the C₁₀-C₁₈ alkyl alkoxy sulfates (especially EO 1-5 ethoxysulfates), C₁₀-C₁₈ alkyl alkoxy carboxylates (especially the EO 1-5ethoxycarboxylates), the C₁₀-C₁₈ alkyl polyglycosides, and theircorresponding sulfated polyglycosides, C₁₂-C₁₈ α-sulfonated fatty acidesters, C₁₂-C₁₈ alkyl and alkyl phenol alkoxylates (especiallyethoxylates and mixed ethoxy/propoxy), C₁₂-C₁₈ betaines andsulfobetaines (“sultaines”), C₁₀-C₁₈ amine oxides, and the like. Thealkyl alkoxy sulfates (AES) and alkyl alkoxy carboxylates (AEC) arepreferred herein. The use of such surfactants in combination with theamine oxide and/or betaine or sultaine surfactants is also preferred,depending on the desires of the formulator. Other conventional usefulsurfactants are listed in standard texts. Particularly usefulsurfactants include the C₁₀-C₁₈ N-methyl glucamides disclosed in U.S.Pat. No. 5, 194,639, Connor et al., issued Mar. 16, 1993.

A wide variety of other ingredients useful in detergent cleaningcompositions can be included in the compositions herein including, forexample, other active ingredients, carriers, hydrotropes, processingaids, dyes or pigments, and solvents for liquid formulations. If anadditional increment of sudsing is desired, suds boosters such as theC₁₀-C₁₆ alkolamides can be incorporated into the compositions, typicallyat about 1% to about 10% levels. The C₁₀-C₁₄ monoethanol and diethanolamides illustrate a typical class of such suds boosters. Use of suchsuds boosters with high sudsing adjunct surfactants such as the amineoxides, betaines and sultaines noted above is also advantageous. Ifdesired, soluble magnesium salts such as MgCl₂, MgSO₄, and the like, canbe added at levels of, typically, from about 0.1% to about 2%, toprovide additional sudsing.

The liquid detergent compositions herein may contain water and othersolvents as carriers. Low molecular weight primary or secondary alcoholsexemplified by methanol, ethanol, propanol, and iso-propanol aresuitable. Monohydric alcohols are preferred for solubilizingsurfactants, but polyols such as those containing from about 2 to about6 carbon atoms and from about 2 to about 6 hydroxy groups (e.g.,1,3-propanediol, ethylene glycol, glycerine, and 1,2-propanediol) canalso be used. The compositions may contain from about 5% to about 90%,typically from about 10% to about 50% of such carriers.

The detergent compositions herein will preferably be formulated suchthat during use in aqueous cleaning operations, the wash water will havea pH between about 6.8 and about 11. Finished products are typicallyformulated at this range. Techniques for controlling pH at recommendedusage levels include the use of, for example, buffers, alkalis, andacids. Such techniques are well known to those skilled in the art.

When formulating the hard surface cleaning compositions and fabriccleaning compositions of the present invention, the formulator may wishto employ various builders at levels from about 5% to about 50% byweight. Typical builders include the 1-10 micron zeolites,polycarboxylates such as citrate and oxydisuccinates, layered silicates,phosphates, and the like. Other conventional builders are listed instandard formularies.

Likewise, the formulator may wish to employ various additional enzymes,such as cellulases, lipases, amylases and proteases in suchcompositions, typically at levels of from about 0.001% to about 1% byweight. Various detersive and fabric care enzymes are well-known in thelaundry detergent art.

Various bleaching compounds, such as the percarbonates, perborates andthe like, can be used in such compositions, typically at levels fromabout 1% to about 15% by weight. If desired, such compositions can alsocontain bleach activators such as tetraacetyl ethylenediamine,nonanoyloxybenzene sulfonate, and the like, which are also known in theart. Usage levels typically range from about 1% to about 10% by weight.

Soil release agents, especially of the anionic oligoester type,chelating agents, especially the aminophosphonates andethylenediaminedisuccinates, clay soil removal agents, especiallyethoxylated tetraethylene pentamine, dispersing agents, especiallypolyacrylates and polyasparatates, brighteners, especially anionicbrighteners, suds suppressors, especially silicones and secondaryalcohols, fabric softeners, especially smectite clays, and the like canall be used in such compositions at levels ranging from about 1% toabout 35% by weight. Standard formularies and published patents containmultiple, detailed descriptions of such conventional materials.

Enzyme stabilizers may also be used in the cleaning compositions. Suchenzyme stabilizers include propylene glycol (preferably from about 1% toabout 10%), sodium formate (preferably from about 0.1% to about 1%) andcalcium formate (preferably from about 0.1% to about 1%).

The present variants are useful in hard surface cleaning compositions.As used herein “hard surface cleaning composition” refers to liquid andgranular detergent compositions for cleaning hard surfaces such asfloors, walls, bathroom tile, and the like. Hard surface cleaningcompositions of the present invention comprise an effective amount ofone or more variants of the present invention, preferably from about0.001% to about 10%, more preferably from about 0.01% to about 5%, morepreferably still from about 0.05% to about 1% by weight of variant ofthe composition. In addition to comprising one or more of the variants,such hard surface cleaning compositions typically comprise a surfactantand a water-soluble sequestering builder. In certain specializedproducts such as spray window cleaners, however, the surfactants aresometimes not used since they may produce a filmy and/or streaky residueon the glass surface.

The surfactant component, when present, may comprise as little as 0.1%of the compositions herein, but typically the compositions will containfrom about 0.25% to about 10%, more preferably from about 1% to about 5%of surfactant.

Typically the compositions will contain from about 0.5% to about 50% ofa detergency builder, preferably from about 1% to about 10%.

Preferably the pH should be in the range of from about 7 to about 12.Conventional pH adjustment agents such as sodium hydroxide, sodiumcarbonate or hydrochloric acid can be used if adjustment is necessary.

Solvents may be included in the compositions. Useful solvents include,but are not limited to, glycol ethers such as diethyleneglycol monohexylether, diethyleneglycol monobutyl ether, ethyleneglycol monobutyl ether,ethyleneglycol monohexyl ether, propyleneglycol monobutyl ether,dipropyleneglycol monobutyl ether, and diols such as2,2,4-trimethyl-1,3-pentanediol and 2-ethyl-1,3-hexanediol. When used,such solvents are typically present at levels of from about 0.5% toabout 15%, more preferably from about 3% to about 11%.

Additionally, highly volatile solvents such as iso-propanol or ethanolcan be used in the present compositions to facilitate faster evaporationof the composition from surfaces when the surface is not rinsed after“full strength” application of the composition to the surface. Whenused, volatile solvents are typically present at levels of from about 2%to about 12% in the compositions.

Hard surface cleaning compositions of the present invention areillustrated by the following examples.

EXAMPLES 1—6

Liquid Hard Surface Cleaning Compositions Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5Ex. 6 G70* + S78* + I79* 0.05% 0.50% 0.02% 0.03% 0.30% 0.05% EDTA — —2.90% 2.90% — — Sodium Citrate — — — — 2.90% 2.90% NaC₁₂ Alkyl-benzene1.95% — 1.95% — 1.95% — sulfonate NaC₁₂ Alkylsulfate — 2.20% — 2.20% —2.20% NaC₁₂ (ethoxy) sulfate — 2.20% — 2.20% — 2.20% C₁₂ Dimethylamineoxide — 0.50% — 0.50% — 0.50% Sodium cumene sulfonate 1.30% — 1.30% —1.30% — Hexyl Carbitol 6.30% 6.30% 6.30% 6.30% 6.30% 6.30% Water 90.4%88.3% 87.53% 85.87% 87.25% 85.85%

All formulas are adjusted to pH 7.

In Examples 1-6, the variants recited in Tables 2-10, and the preferredvariants cited herein, among others, are substituted for G70*+S78*+I79*,with substantially similar results.

In another embodiment of the present invention, dishwashing compositionscomprise one or more variants of the present invention. As used herein,“dishwashing composition” refers to all forms of compositions forcleaning dishes including, but not limited to, granular and liquidforms. Dishwashing compositions of the present invention are illustratedby the following examples.

EXAMPLES 7-10

Liquid Dish Detergent Ex. 7 Ex. 8 Ex. 9 Ex. 10 G70* + L75* + N76* +N77* + 0.05% 0.50% 0.02% 0.40% S78* + I79* + G80* + V81* + L82* C₁₂—C₁₄N-methyl glucamide 0.90% 0.90% 0.90% 0.90% C₁₂ ethoxy (1) sulfate 12.0%12.0% 12.0% 12.0% 2-Methyl undecanoic acid 4.50% 4.50% 4.50% 4.50% C₁₂ethoxy (2) carboxylate 4.50% 4.50% 4.50% 4.50% C₁₂ alcohol ethoxylate(4) 3.00% 3.00% 3.00% 3.00% C₁₂ amine oxide 3.00% 3.00% 3.00% 3.00%Sodium cumene sulfonate 2.00% 2.00% 2.00% 2.00% Ethanol 4.00% 4.00%4.00% 4.00% Mg²⁺ (as MgCl₂) 0.20% 0.20% 0.20% 0.20% Ca²⁺ (as CaCl₂)0.40% 0.40% 0.40% 0.40% Water 65.45% 65%   65.48% 65.1%

All formulas are adjusted to pH 7.

In Examples 7-10, the variants recited in Tables 2-10, and the preferredvariants cited herein, among others, are substituted forG70*+L75*+N76*+N77*+S78*+I79*+G80*+V81*+L82*, with substantially similarresults.

Liquid fabric cleaning compositions of the present invention areillustrated by the following examples.

EXAMPLES 11-13

Liquid Fabric Cleaning Compositions Ex. 11 Ex. 12 Ex. 13 G70* 0.05%0.03% 0.30% Sodiuam C₁₂—C₁₄ alkyl sulfate 20.0% 20.0% 20.0% 2-Butyloctanoic acid 5.0% 5.0% 5.0% Sodium citrate 1.0% 1.0% 1.0% C₁₀ Alcoholethoxylate (3) 13.0% 13.0% 13.0% Monoethanolamine 2.50% 2.50% 2.50%Water/propylene glycol/ethanol (100:1:1) 58.45% 53.47% 58.20%

In Examples 11-13, the variants recited in Tables 2-10, and thepreferred variants cited herein, among others, are substituted for G70*,with substantially similar results.

Personal Care Compositions

The present variants are particularly suited for use in personal carecompositions such as, for example, leave-on and rinse-off hairconditioners, shampoos, leave-on and rinse-off acne compositions, facialmilks and conditioners, shower gels, soaps, foaming and non-foamingfacial cleansers, cosmetics, hand, facial, and body lotions andmoisturizers, leave-on facial moisturizers, cosmetic and cleansingwipes, oral care compositions, and contact lens care compositions. Thepresent personal care compositions comprise one or more variants of thepresent invention and a personal care carrier.

To illustrate, the present variants are suitable for inclusion in thecompositions described in the following references: U.S. Pat. No.5,641,479, Linares et al., issued Jun. 24, 1997 (skin cleansers); U.S.Pat. No. 5,599,549, Wivell et al., issued Feb. 4, 1997 (skin cleansers);U.S. Pat. No. 5,585,104, Ha et al., issued Dec. 17, 1996 (skincleansers); U.S. Pat. No. 5,540,852, Kefauver et al., issued Jul. 30,1996 (skin cleansers); U.S. Pat. No. 5,510,050, Dunbar et al., issuedApr. 23, 1996 (skin cleansers); U.S. Pat. No. 5,612,324, Guang Lin etal., issued Mar. 18, 1997 (anti-acne preparations); U.S. Pat. No.5,587,176, Warren et al., issued Dec. 24, 1996 (anti-acne preparation;U.S. Pat. No. 5,549,888, Venkateswaran, issued Aug. 27, 1996 (anti-acnepreparations); U.S. Pat. No. 5,470,884, Corless et al., issued Nov. 28,1995 (anti-acne preparations); U.S. Pat. No. 5,650,384, Gordon et al.,issued Jul. 22, 1997 (shower gels); U.S. Pat. No. 5,607,678, Moore etal., issued Mar. 4, 1997 (shower gels); U.S. Pat. No. 5,624,666,Coffindaffer et al., issued Apr. 29, 1997 (hair conditioners and/orshampoos); U.S. Pat. No. 5,618,524, Bolich et al., issued Apr. 8, 1997(hair conditioners and/or shampoos); U.S. Pat. No. 5,612,301, Inman,issued Mar. 18, 1997 (hair conditioners and/or shampoos); U.S. Pat. No.5,573,709, Wells, issued Nov. 12, 1996 (hair conditioners and/orshampoos); U.S. Pat. No. 5,482,703, Pings, issued Jan. 9, 1996 (hairconditioners and/or shampoos); U.S. Pat. No. Re. 34,584, Grote et al.,Reissued Apr. 12, 1994 (hair conditioners and/or shampoos); U.S. Pat.No. 5,641,493, Date et al., issued Jun. 24, 1997 (cosmetics); U.S. Pat.No. 5,605,894, Blank et al., issued Feb. 25, 1997 (cosmetics); U.S. Pat.No. 5,585,090, Yoshioka et al., issued Dec. 17, 1996 (cosmetics); U.S.Pat. No. 4,939,179, Cheney et al., issued Jul. 3, 1990 (hand, face,and/or body lotions); U.S. Pat. No. 5,607,980, McAtee et al., issuedMar. 4, 1997 (hand, face, and/or body lotions); U.S. Pat. No. 4,045,364,Richter et al., issued Aug. 30, 1977 (cosmetic and cleansing wipes);European Patent Application, EP 0 619 074, Touchet et al., publishedOct. 12, 1994 (cosmetic and cleansing wipes); U.S. Pat. No. 4,975,217,Brown-Skrobot et al., issued Dec. 4, 1990 (cosmetic and cleansingwipes); U.S. Pat. No. 5,096,700, Seibel, issued Mar. 17, 1992 (oralcleaning compositions); U.S. Pat. No. 5,028,414, Sampathkumar, issuedJul. 2, 1991 (oral cleaning compositions); U.S. Pat. No. 5,028,415,Benedict et al., issued Jul. 2, 1991 (oral cleaning compositions); U.S.Pat. No. 5,028,415, Benedict et al., issued Jul. 2, 1991 (oral cleaningcompositions); U.S. Pat. No. 4,863,627, Davies et al., Sep. 5, 1989(contact lens cleaning solutions); U.S. Pat. No. Re. 32,672, Huth et al,reissued May 24, 1988 (contact lens cleaning solutions); and U.S. Pat.No. 4,609,493, Schafer, issued Sep. 2, 1986 (contact lens cleaningsolutions).

To further illustrate oral cleaning compositions of the presentinvention, a pharmaceutically-acceptable amount of one or more variantsof the present invention are included in compositions useful forremoving proteinaceous stains from teeth or dentures. As used herein,“oral cleaning compositions” refers to dentifrices, toothpastes,toothgels, toothpowders, mouthwashes, mouth sprays, mouth gels, chewinggums, lozenges, sachets, tablets, biogels, prophylaxis pastes, dentaltreatment solutions, and the like. Preferably, the oral cleaningcompositions comprise from about 0.0001% to about 20% of one or morevariants of the present invention, more preferably from about 0.001% toabout 10%, more preferably still from about 0.01% to about 5%, by weightof the composition, and a pharmaceutically-acceptable carrier. As usedherein, “pharmaceutically-acceptable” means that drugs, medicaments orinert ingredients which the term describes are suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, incompatibility, instability, irritation, allergic response,and the like, commensurate with a reasonable benefit/risk ratio.

Typically, the pharmaceutically-acceptable oral cleaning carriercomponents of the oral cleaning components of the oral cleaningcompositions will generally comprise from about 50% to about 99.99%,preferably from about 65% to about 99.99%, more preferably from about65% to about 99%, by weight of the composition.

The pharmaceutically-acceptable carrier components and optionalcomponents which may be included in the oral cleaning compositions ofthe present invention are well known to those skilled in the art. A widevariety of composition types, carrier components and optional componentsuseful in the oral cleaning compositions are disclosed in the referencescited hereinabove.

In another embodiment of the present invention, denture cleaningcompositions for cleaning dentures outside of the oral cavity compriseone or more variants of the present invention. Such denture cleaningcompositions comprise an effective amount of one or more of thevariants, preferably from about 0.0001% to about 50% of one or more ofthe variants, more preferably from about 0.001% to about 35%, morepreferably still from about 0.01% to about 20%, by weight of thecomposition, and a denture cleansing carrier. Various denture cleansingcomposition formats such as effervescent tablets and the like are wellknown in the art (see, e.g., U.S. Pat. No. 5,055,305, Young), and aregenerally appropriate for incorporation of one or more of the variantsfor removing proteinaceous stains from dentures.

In another embodiment of the present invention, contact lens cleaningcompositions comprise one or more variants of the present invention.Such contact lens cleaning compositions comprise an effective amount ofone or more of the variants, preferably from about 0.01% to about 50% ofone or more of the variants, more preferably from about 0.01% to about20%, more preferably still from about 1% to about 5%, by weight of thecomposition, and a contact lens cleaning carrier. Various contact lenscleaning composition formats such as tablets, liquids and the like arewell known in the art and are generally appropriate for incorporation ofone or more variants of the present invention for removing proteinaceousstains from contact lenses.

The contact lens cleaning composition embodiment of the presentinvention is illustrated by Examples 14-17.

EXAMPLES 14-17

Contact Lens Cleaning Solution Ex. 14 Ex. 15 Ex. 16 Ex. 17 N76* 0.01%0.5% 0.1% 2.0% Glucose 50.0% 50.0% 50.0% 50.0% Nonionic surfactant 2.0%2.0% 2.0% 2.0% (polyoxyethlene- polyoxypropylene copolymer) Anionicsurfactant 1.0% 1.0% 1.0% 1.0% (polyoxyethylene- alkylphenylether sodiumsulfricester) Sodium Chloride 1.0% 1.0% 1.0% 1.0% Borax 0.30% 0.30%0.30% 0.30% Water 45.69% 45.20% 45.60% 43.70%

In Examples 14-17, the variants recited in Tables 2-10, and thepreferred variants cited herein, among others, are substituted for N76*,with substantially similar results.

Examples 18-21 illustrate the use of the present variants in bodywashproducts:

EXAMPLES 18-21

Bodywash Products Ex. 18 Ex. 19 Ex. 20 Ex. 21 Water 62.62% 65.72% 57.72%60.72% Disodium EDTA 0.2% 0.2% 0.2% 0.2% Glycerine 3.0% 3.0% 3.0% 3.0%Polyquaternium 10 0.4% 0.4% 0.4% 0.4% Sodium laureth sulphate 12.0%12.0% 12.0% 12.0% Cocamide MEA 2.8% 2.8% 2.8% 2.8% Sodiumlauraphoacetate 6.0% 6.0% 6.0% 6.0% Myristic Acid 1.6% 1.6% 1.6% 1.6%Magnesium sulphate 0.3% 0.3% 0.3% 0.3% heptahydrate Trihydroxystearin0.5% 0.5% 0.5% 0.5% PEG-6 caprylic/capric 3.0% — — — triglyceridesSucrose polyesters of cottonate 3.0% — — — fatty acid Sucrose polyestersof behenate 3.0% — 4.0% — fatty acid Petrolatum — 4.0% 8.0% — MineralOil — — — 6.0% DMDM Hydantoin 0.08% 0.08% 0.08% 0.08% L75* + N76* +N77* + S78* + 0.1% 2.0% 2.0% 5.0% I79* + G80* + V81* + L82* Citric Acid1.40% 1.40% 1.40% 1.40%

In Examples 18-21, the variants recited in Tables 2-10, and thepreferred variants cited herein, among others, are substituted forL75*+N76*+N77*+S78*+179*+G80*+V81*+L82*, with substantially similarresults.

Examples 18-21 illustrate the use of the present variants in facewashproducts:

EXAMPLES 22-25

Facewash Products Ex. 22 Ex. 23 Ex. 24 Ex. 25 Water 66.52% 65.17% 68.47%68.72% Disodium EDTA 0.1% 0.1% 0.2% 0.2% Citric Acid — — 1.4% 1.4%Sodium Laureth-3 Sulfate 3.0% 3.5% — — Sodium Laureth-4 Carboxylate 3.0%3.5% — — Laureth-12 1.0% 1.2% — — Polyquaternium 10 — — 0.4% 0.4%Polyquaternium 25 0.3% 0.3% — — Glycerine 3.0% 3.0% 3.0% 3.0% SodiumLauroamphoacetate — — 6.0% 6.0% Lauric Acid 6.0% 6.0% 3.0% 3.0% MyristicAcid — — 3.0% 3.0% Magnesium sulphate heptahydrate 2.3% 2.0% 2.0% 2.0%Triethanol amine 4.0% 4.0% 4.0% 4.0% Trihydroxystearin 0.5% 0.5% 0.5%0.5% Sucrose polyesters of behenate 2.0% 2.0% — — fatty acid Sucrosepolyesters of cottonate 3.0% 2.0% — — fatty acid PEG-6 caprylic/capric —— — 2.0% triglycerides Petrolatum — — 4.0% — Mineral Oil — — — 2.0%Cocamidopropyl betaine 2.0% 3.0% 1.8% 1.8% Lauryl dimethylamine oxide1.0% 1.2% 1.2% 1.2% Dex Panthenol 1.0% 0.25% 0.25% — DMDM Hydantoin0.08% 0.08% 0.08% 0.08% L75* 1.0% 2.0% 0.5% 0.5% Fragrance 0.2% 0.2%0.2% 0.2%

In Examples 22-25, the variants recited in Tables 2-10, and thepreferred variants cited herein, among others, are substituted for L75*,with substantially similar results. Examples 26-27 illustrate the use ofthe present variants in leave-on skin moisturizing compositions:

EXAMPLES 26-27

Leave-on Skin Moisturizing Composition Ex. 26 Ex. 27 Glycerine 5.0% —Stearic acid 3.0% — C₁₁₋₁₃ Isoparaffin 2.0% — Glycol stearate 1.5% —Propylene glycol — 3.0% Mineral oil 1.0% 10.0% Sesame oil — 7.0%Petrolatum — 1.8% Triethanolamine 0.7% — Cetyl acetate 0.65% — Glycerylstearate 0.48% 2.0% TEA stearate — 2.5% Cetyl alcohol 0.47% — Lanolinalcohol — 1.8% DEA - cetyl phosphate 0.25% — Methylparaben 0.2% 0.2%Propylparaben 0.12% 0.1% Carbomer 934 0.11% — Disodium EDTA 0.1% — L82*0.1% 0.5% Water 84.32% 71.1%

In Examples 26-27, the variants recited in Tables 2-10, and thepreferred variants cited herein, among others, are substituted for L82*,with substantially similar results.

Example 28 illustrates the use of the present variants in cleansing wipecompositions:

EXAMPLE 28

Cleansing Wipe Composition Propylene Glycol 1.0% Ammonium lauryl sulfate0.6% Succinic acid 4.0% Sodium succinate 3.2% Triclosan ® 0.15% S78*0.05% Water 91.0%

The above composition is impregnated onto a woven absorbent sheetcomprised of cellulose and/or polyester at about 250 %, by weight of theabsorbent sheet.

In Example 28, the variants recited in Tables 2-10, and the preferredvariants cited herein, among others, are substituted for S78*, withsubstantially similar results.

1 1 275 PRT Bacillus amyloliquefaciens 1 Ala Gln Ser Val Pro Tyr Gly ValSer Gln Ile Lys Ala Pro Ala Leu 1 5 10 15 His Ser Gln Gly Tyr Thr GlySer Asn Val Lys Val Ala Val Ile Asp 20 25 30 Ser Gly Ile Asp Ser Ser HisPro Asp Leu Lys Val Ala Gly Gly Ala 35 40 45 Ser Met Val Pro Ser Glu ThrAsn Pro Phe Gln Asp Asn Asn Ser His 50 55 60 Gly Thr His Val Ala Gly ThrVal Ala Ala Leu Asn Asn Ser Ile Gly 65 70 75 80 Val Leu Gly Val Ala ProSer Ala Ser Leu Tyr Ala Val Lys Val Leu 85 90 95 Gly Ala Asp Gly Ser GlyGln Tyr Ser Trp Ile Ile Asn Gly Ile Glu 100 105 110 Trp Ala Ile Ala AsnAsn Met Asp Val Ile Asn Met Ser Leu Gly Gly 115 120 125 Pro Ser Gly SerAla Ala Leu Lys Ala Ala Val Asp Lys Ala Val Ala 130 135 140 Ser Gly ValVal Val Val Ala Ala Ala Gly Asn Glu Gly Thr Ser Gly 145 150 155 160 SerSer Ser Thr Val Gly Tyr Pro Gly Lys Tyr Pro Ser Val Ile Ala 165 170 175Val Gly Ala Val Asp Ser Ser Asn Gln Arg Ala Ser Phe Ser Ser Val 180 185190 Gly Pro Glu Leu Asp Val Met Ala Pro Gly Val Ser Ile Gln Ser Thr 195200 205 Leu Pro Gly Asn Lys Tyr Gly Ala Tyr Asn Gly Thr Ser Met Ala Ser210 215 220 Pro His Val Ala Gly Ala Ala Ala Leu Ile Leu Ser Lys His ProAsn 225 230 235 240 Trp Thr Asn Thr Gln Val Arg Ser Ser Leu Glu Asn ThrThr Thr Lys 245 250 255 Leu Gly Asp Ser Phe Tyr Tyr Gly Lys Gly Leu IleAsn Val Gln Ala 260 265 270 Ala Ala Gln 275

What is claimed is:
 1. A serine protease variant having a modified aminoacid sequence of a wild-type amino acid sequence comprising asubstitution by a substituting amino acid in at least one positioncorresponding to positions 75-76 and 78-81 of subtilisin BPN′ wherein:(a) when the substitution occurs at position 75, the substituting aminoacid is selected from the group consisting of Ala, Arg, Asn, Cys, Gly,Phe, His, Ile, Lys, Met, Gln, Ser, Thr, Trp, Tyr, and Val; (b) when thesubstitution occurs at position 76, the substituting amino acid isselected from the group consisting of Ala, Arg, Cys, Ile, Leu, Met, GlnSer, Thr, Trp, Tyr, and Val; (c) when the substitution occurs atposition 78, the substituting amino acid is selected from the groupconsisting of Ala, Arg, Asn, Cys, Gly, Phe, His, Ile, Lys, Leu, Met,Pro, Gln, Thr, Trp, Tyr, and Val; (d) when the substitution occurs atposition 79, the substituting amino acid is selected from the groupconsisting of Ala, Arg, Asn, Cys, Gly, Phe, His, Lys, Leu, Met, Pro,Gln, Ser, Thr, Trp, Tyr, and Val; (e) when the substitution occurs atposition 80, the substituting amino acid is selected from the groupconsisting of Ala, Arg, Asn, Cys, Phe, His, Ile, Lys, Leu, Met, Pro,Gln, Ser, Thr, Trp, Tyr, and Val; and, (f) when the substitution occursat position 81, the substituting amino acid is selected from the groupconsisting of Ala, Arg, Asn, Cys, Gly, Phe, His, Ile, Lys, Leu, Met,Pro, Gln Ser, Thr, Trp, and Tyr.
 2. A variant according to claim 1wherein the serine protease is selected from the group consisting ofsubtilisin BPN′, subtilisin Carlsberg, subtilisin DY, subtilisin 309,proteinase K, and thermitase.
 3. A variant according to claim 2 whereinthe serine protease is subtilisin BPN′.
 4. A variant of claim 3 whereinthe substitution is of one or more of positions 75, 76 and 78-81.
 5. Avariant according to claim 1 further comprising one or more stabilizingmutations.
 6. A variant according to claim 5 wherein the stabilizingmutations are selected from the group consisting of 107V, K213R, Y217L,Y217K, N218S, G169A, M50F, Q19E, P5A, S9A, I31L, E156S, G169A, N212G,S188P, T254A, S3C+Q206C, and Q271E.
 7. A variant according to claim 6wherein the stabilizing mutation is Y217L.
 8. A mutant serine proteasegene encoding the variant according to claim
 1. 9. A cleaningcomposition comprising a variant according to claim 1 and a cleaningcomposition carrier.
 10. A personal care composition comprising avariant according to claim 1 and a personal care carrier.
 11. A personalcare composition according to claim 10 which is selected from the groupconsisting of oral cleaning compositions, contact lens cleaningcompositions, hair care compositions, beauty care compositions, and skincare compositions.